Peripheral Artery Disease - Peripheral Arterial Disease

Peripheral artery disease (PAD) is a narrowing of the arteries other than those that supply the heart or the brain. When narrowing occurs in the heart it is called coronary artery disease while in the brain it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved. The classic symptom is leg pain when walking which resolves with rest, known as intermittent claudication. Other symptoms including skin ulcers, bluish skin, cold skin, or poor nail and hair growth may occur in the affected leg. Complications may include an infection or tissue death which may require amputation; coronary artery disease, or stroke. Up to 50% of cases of PAD are without symptoms.

The main risk factor is cigarette smoking. Other risk factors include diabetes, high blood pressure, and high blood cholesterol. The underlying mechanism is usually atherosclerosis. Other causes include artery spasm. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.

It is unclear if screening for disease is useful as it has not been properly studied. In those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy improves outcomes. Medications, including statins, ACE inhibitors, and cilostazol also may help. Aspirin does not appear to help those with mild disease but is usually recommended in those with more significant disease. Anticoagulants such as warfarin are not typically of benefit. Procedures used to treat the disease include bypass grafting, angioplasty, and atherectomy.

In 2010 about 202 million people had PAD worldwide. In the developed world it affects about 5.3% of 45 to 50 years olds and 18.6% of 85- to 90-year-olds. In the developing world it affects 4.6% of people between the ages of 45 to 50 and 15% of people between the ages of 85 to 90. In the developed world PAD is equally common among men and women while in the developing world women are more commonly affected. In 2013 PAD resulted in about 41,000 deaths up from 16,000 deaths in 1990.

Signs and symptoms

Up to 50% of people with PAD may have no symptoms. Symptoms of PAD in the legs and feet are generally divided into 2 categories:

1. Intermittent claudicationâ€"pain in muscles when walking or using the affected muscles that is relieved by resting those muscles. This is due to the unmet oxygen demand in muscles with use in the setting of inadequate blood flow.
2. Critical limb ischemia, consisting of:

• Rest pain, a pain in the soles of the feet, particularly when the feet are elevated, such as when in bed.
• Tissue loss, consisting of arterial insufficiency ulcers, which are sores or wounds that heal slowly or not at all, and gangrene.

Medical signs of PAD in the legs, due to inadequate perfusion, include:

• Noticeable change in color â€" blueness, or in temperature (coolness) when compared to the other limb.
• Buerger's test can check for pallor on elevation of limb and redness (rubor) on a change to a sitting position, in an assessment of arterial sufficiency.
• Diminished hair and nail growth on affected limb and digits

PAD in other parts of the body depends on the organ affected. Renal artery disease can cause renovascular hypertension. Carotid artery disease can cause strokes and transient ischemic attacks.

Causes

Risk factors contributing to PAD are the same as those for atherosclerosis:

• Smoking â€" tobacco use in any form is the single most important modifiable cause of PAD internationally. Smokers have up to a tenfold increase in relative risk for PAD in a dose-response relationship. Exposure to second-hand smoke from environmental exposure has also been shown to promote changes in blood vessel lining (endothelium) which is a precursor to atherosclerosis. Smokers are 2 to 3 times more likely to have lower extremity peripheral arterial disease than coronary artery disease. More 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.
• Diabetes mellitus â€" causes between two and four times increased risk of PAD by causing endothelial and smooth muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
• Dyslipidemia â€" a high level of low-density lipoprotein (LDL cholesterol) and a low level of high-density lipoprotein (HDL cholesterol) in the blood) - elevation of total cholesterol, LDL cholesterol, and triglyceride levels each have been correlated with accelerated PAD. Correction of dyslipidemia by diet and/or medication is associated with a major improvement in rates of heart attack and stroke.
• Hypertension â€" elevated blood pressure is correlated with an increase in the risk of developing PAD, as well as in associated coronary and cerebrovascular events (heart attack and stroke). Hypertension increased the risk of intermittent claudication 2.5- to 4-fold in men and women, respectively.
• Risk of PAD also increases in individuals who are over the age of 50, male, obese, heart attack, or stroke or with a family history of vascular disease.
• Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, hyperviscosity, hypercoagulable state.

Risk factors

Peripheral arterial disease is more common in the following populations of people:

• 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 the age of 50 to 69 and 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 10%-20%
• All people who have previously experienced chest pain

Diagnosis

Upon suspicion of PAD, the first-line study is the ankle brachial pressure index (ABPI/ABI). When the blood pressure readings in the ankles is lower than that in the arms, blockages in the arteries which provide blood from the heart to the ankle are suspected. Normal ABI range of 1.00 to 1.40.The patient is diagnosed with PAD when the ABI is ≤ 0.90 . ABI values of 0.91 to 0.99 are considered ‘‘borderline’’ and values >1.40 indicate noncompressible arteries. PAD is graded as mild to moderate if the ABI is between 0.41 and 0.90, and an ABI less than 0.40 is suggestive of severe PAD. These relative categories have prognostic value.

In people with suspected PAD but normal resting ABIs, exercise testing of ABI can be done. A base line ABI is obtained prior to 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 (or a maximum of 5 minutes), following which the ankle pressure is again measured. A decrease in ABI of 15%-20% would be diagnostic of PAD.

It is possible for conditions which stiffen the vessel walls (such as calcifications that occur in the setting of long term diabetes) to produce false negatives usually, but not always, indicated by abnormally high ABIs (> 1.40). Such results and suspicions merit further investigation and higher level studies.

If ABIs are abnormal the next step is generally a lower limb doppler ultrasound examination to look at site and extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radiodense contrast agent an X-ray is taken. Any flow limiting stenoses found in the x-ray can be identified and treated by atherectomy, angioplasty or stenting. Contrast angiography is the most readily available and widely used imaging technique.

Modern multislice computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography.

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 to provide pictures of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution three-dimensional (3D) imaging of the entire abdomen, pelvis and lower extremities in one sitting.

Classification

Peripheral artery occlusive disease is commonly divided in the Fontaine stages, introduced by René Fontaine in 1954 for chronic limb ischemia:

• Stage I: Asymptomatic, incomplete blood vessel obstruction
• Stage II: Mild claudication pain in limb

• Stage IIA: Claudication when walking a distance of greater than 200 meters
• Stage IIB: Claudication when walking a distance of less than 200 meters

• Stage III: Rest pain, mostly in the feet
• Stage IV: Necrosis and/or gangrene of the limb

A classification introduced by Robert B. Rutherford in 1986 and revised in 1997 consists of four grades and seven categories:

• 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 ulcer of the digits of the foot
• Grade IV, Category 6: Major tissue loss; Severe ischemic ulcers or frank gangrene

The TASC (and TASC II) classification suggested PAD treatment by severity of disease seen on angiogram. More recently classifications, such as the Society for Vascular Surgery "Wound, Ischemia and Foot Infection" (WIFI) classification, take into account that ischemia and angiographic disease patterns are not the only determinants of amputation risk.

Screening

It is not clear if screening for disease is useful as it has not been properly studied.

Treatment

Depending on the severity of the disease, the following steps can be taken, according to the following guidelines:

Lifestyle changes

• Smoking cessation (cigarettes promote PAD and are a risk factor for cardiovascular disease).
• Management of diabetes.
• Management of hypertension.
• Management of high cholesterol, and medication with antiplatelet drugs. Medication with aspirin, clopidogrel and statins, which reduce clot formation and cholesterol levels, respectively, can help with disease progression and address the other cardiovascular risks that the patient is likely to have.
• Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, 3 to 4 times per week) has been reviewed as another treatment with a number of positive outcomes including reduction in cardiovascular events and improved quality of life.

Medication

Cilostazol or pentoxifylline can improve symptoms in some.

Treatment with other drugs or vitamins are unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B-12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".

Revascularization

After a trial of the best medical treatment outline above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss such as wound and infection severity.

• Angioplasty (PTA, or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but angioplasty 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 outcome following revascularization are length of lesion, and number of lesions.
• Atherectomy, in which the plaque is scraped off of 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 adequate venous conduit is unavailable.
• When gangrene has set in, amputation is required to prevent infected tissues from causing sepsis a life-threatening illness.
• Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.

Guidelines

An updated consensus 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.

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 the Ankle brachial pressure index (ABPI). Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".

There is a low risk that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. 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 peripheral artery disease in the general population is 12â€"14%, affecting up to 20% of those over 70; 70%â€"80% of affected individuals are asymptomatic; only a minority ever require revascularisation or amputation. Peripheral artery disease affects 1 in 3 diabetics over the age of 50.

In the USA peripheral arterial disease affects 12â€"20 percent of Americans age 65 and older. Approximately 10 million Americans have PAD. Despite its prevalence and cardiovascular risk implications, only 25 percent of PAD patients are undergoing treatment.

The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40â€"55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined, and the age of the population being studied. Diagnosis is critical, as people with PAD have a four to five times higher risk of heart attack or stroke.

The Diabetes Control and Complications Trial, and the U.K. 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. It may be that pathologic changes occurring in small vessels are more sensitive to chronically elevated glucose levels than is atherosclerosis occurring in larger arteries.

Research

In those who have developed critically poor blood flow to the legs it is unclear if autotransplantation of autologous mononuclear cells is useful or not.

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, however the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2015, a second trial is being conducted regarding the optimal revascularization for severe PAD.

In 2011 pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for treatment of peripheral artery disease, including the advanced stage of critical limb ischemia.