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Peripheral Arterial Disease: Insights into Diagnosis and Management

Overall, the presence of these risk factors makes the development of atherosclerosis and PAD more likely. An example of this is in a study, people with 6 or more risk factors had a 10-20 fold increase in the PAD rate than those with no risk factors.

High blood sugar associated with diabetes, whether type 1 or type 2, can damage the arteries and lead to atherosclerosis as well. PAD is way more common among diabetics, and approximately one in three diabetics over the age of 50 has PAD because they typically have factors that put them at risk for the disease.

Smoking causes a person to have four times the risk of heart disease and peripheral artery disease than the risk in a non-smoker. This involves any tobacco or long-term exposure to second-hand smoke. It speeds up the damage to your arteries due to the build-up of plaque and atherosclerosis.

High blood cholesterol, one of the main reasons for atherosclerosis, is caused by too much of a fatty substance called cholesterol in your blood. Cholesterol and fat make up blood substances called lipids. The most common are high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol. HDL cholesterol is known as good cholesterol because it helps keep the bad cholesterol from building up in the arteries. LDL cholesterol is considered bad cholesterol because a high content of it can result in cholesterol being deposited in the arteries.

High blood pressure, high blood cholesterol, and smoking are all major modifiable risk factors. High blood pressure or hypertension is a chief factor in narrowing and hardening of the arteries. According to the National Heart Lung and Blood Institute (NHLBI), 70 million American adults (29%) have high blood pressure. High blood pressure increases the force of blood flowing through your arteries and can damage artery walls, which can ultimately cause them to narrow and harden.

Without the presence of risk factors, atherosclerosis and PAD would not occur. There are, of course, non-modifiable and modifiable risk factors. Non-modifiable risk factors are age and family history. Age is the strongest known risk factor for PAD and atherosclerosis, mainly since damage to the arteries resulting from the build-up of fatty deposits takes time to happen. 65% of people with PAD are older than 60. The risk of artery disease raises the more you have with age. Family history can put you at risk more than those with relatives who have had heart and blood vessel disease. This is where people who have a parent, brother, or sister with the disease are at greater risk for getting it. This can be due to genes, but there is still ongoing research whether other races, for example, Hispanic or Asian, have a higher risk.

PAD is caused by “hardening of the arteries,” medical wording for atherosclerosis. Atherosclerosis is where fatty substances and a build-up of cholesterol are collected in the walls of arteries. This plaque build-up can cause narrowed or blocked arteries. PAD is same to coronary artery disease, where the buildup of plaque in the arteries to the heart can cause chest pain, heart attacks, and other serious issues. Its symptoms like leg pain during exercise and rest, claudication, and possible amputation of the leg or foot occur because blood flow is restricted to certain areas of the leg and/or feet.

Peripheral arterial disease is the progressively building up of plaque in the arteries that carry blood to the head, organs, and your limbs. When arteries harden and build up plaque, blood flow to the brain, stomach, limbs, and feet may be slowed or stopped. The condition is also known as peripheral arterial disease (PAD).

Diagnosis of Peripheral Arterial Disease

The presence of peripheral pulses can be assessed easily and quickly in an outpatient setting. However, pulse examination suffers from significant inter-observer variability and has a low sensitivity for detecting PAD. An absent pulse has been correlated with a high degree of stenosis or occlusion of an artery and advanced PAD. The ankle-brachial pressure index (ABPI) is a simple, noninvasive test that provides both an accurate and reproducible assessment of the presence and severity of PAD.

Clinical evaluation has traditionally been the sole means of both diagnosing and assessing the severity of PAD. The characteristic symptom is intermittent claudication, an aching pain in the muscles of the leg brought on by exercise and relieved by rest. Unfortunately, the classic symptom may not be present in all patients and is frequently dismissed as old age or arthritis. A careful history may uncover atypical leg symptoms or functional impairment that can be attributed to PAD. A physical examination may show evidence of an arterial bruit in the abdomen or femoral arteries, although auscultation of bruits has a low sensitivity and specificity for diagnosing PAD.

Peripheral arterial disease (PAD) is a common but frequently underdiagnosed condition. In addition to symptoms of intermittent claudication, disability, and impaired quality of life, patients with PAD have a greatly increased risk of cardiovascular ischemic events and death. It is important to recognize the presence of PAD, even when patients are asymptomatic or have atypical leg symptoms, in order to modify risk factors and medical therapies appropriately. Unfortunately, early recognition of PAD remains the most challenging aspect of the disease’s management. In many patients, the diagnosis is made incidentally by an abnormal finding on a pulse examination or an ankle-brachial pressure index done in the investigation of other complaints. In recent years, a number of consensus statements and guidelines have been published about the diagnosis and treatment of PAD. The most detailed recommendations for clinical trials have been published by the American Heart Association (AHA) in 1998. These recommendations define the anatomic and functional criteria for diagnosing PAD in various arterial beds using non-invasive and invasive testing.

Clinical Evaluation

Patients with pedal pulses and no specific symptoms or signs of PAD may, in certain circumstances, not require further investigation if there are no significant cardiovascular risk factors and no evidence of CVD at other arterial sites. However, the increasing age of the PAD population and the high risk of cardiovascular events in this group of patients would suggest that general cardiovascular risk assessment and screening for asymptomatic CVD is warranted. This may help to limit the extent of further investigation to more clearly defined groups of patients with PAD.

Often, patients with PAD have a history of coronary heart disease, cerebrovascular or carotid artery disease, or abdominal aortic aneurysm. In this group of patients, non-invasive testing to detect asymptomatic CVD may be determined by the findings of the clinical evaluation. Symptoms of intermittent claudication give insight into the overall functional capacity of the patient. They are often, but not always, indicative of the severity of PAD. Other lower extremity symptoms such as pain at rest and ulcers or gangrene are indicative of critical limb ischemia, a severe and advanced form of PAD. The presence of absent or diminished pulses, characteristic bruits, and an abdominal bruit or the detection of hypertension or brachial-ankle pressure gradient will suggest the presence of hemodynamically significant aorto-iliac disease. These patients may often be referred for further non-invasive testing such as Doppler ultrasound or MR angiography.

Peripheral arterial disease (PAD) should be considered as a marker for widespread atherosclerosis and is associated with symptomatic cardiovascular disease (CVD) in other territories in greater than 50% of patients. It is for this reason that patients with PAD should be comprehensively evaluated for other manifestations of CVD, including ischemic heart disease, aortic disease, and cerebrovascular disease.

Imaging Techniques

Magnetic Resonance Imaging has not been widely used and is primarily used for below knee imaging. High-quality images can be obtained with a high resolution and it is free from ionizing radiation which is a bonus especially in younger patients. The technology is expensive and time-consuming and is not widely available but it may have a role in the future.

CT angiography is a non-invasive and rapid way to image the blood vessels. The efficiency of the machines and skill of the operators mean that high-quality images can be obtained and a large amount of information be given in a short time. Development in technology will mean that this investigation will play a key role in diagnosing PAD.

Duplex ultrasound is the most commonly used and a combination of B mode imaging which gives a two-dimensional picture of a vessel and Doppler mode which provides information on blood flow. It is an easily accessible investigation which is highly operator dependent. In a good lab, it can provide clear images on most of the arteries both above and below the knee. However, it is restricted in the more obese patient and those with severe peripheral edema.

Imaging is an important part of diagnosing disease. The anatomical location and extent of the disease in the peripheral arteries need to be known before treatment can be planned. It has been said that the angiogram is the biopsy for PAD because it gives the definitive answer on whether a lesion is significant. Plain film radiography with use of custom preparation of contrast medium can give useful information but modern vascular investigations mainly rely on Duplex ultrasound, Computed Tomography (CT) and Magnetic Resonance Imaging (MRI).

Laboratory Tests

Laboratory tests are not useful for establishing the diagnosis of peripheral arterial disease (PAD), but they may be helpful for identifying the presence of risk factors and comorbid conditions. Measurement of cholesterol and glucose levels is important, given the association of dyslipidemia and diabetes with PAD. The ankle brachial pressure index (ABPI) is a valuable diagnostic tool for PAD, but also provides information on cardiovascular risk. A reduced ABPI is associated with increased risk of cardiovascular events and mortality, even in the absence of symptomatic cardiovascular disease. Although it is possible to obtain a rough estimate of the ABPI by measuring blood pressures in the brachial arteries and ankles with a sphygmomanometer, the most reliable and reproducible results are obtained using a Doppler ultrasound probe. This involves measurement of systolic pressures in the posterior tibial and dorsalis pedis arteries and calculation of the ABPI by dividing the higher pressure in either the posterior tibial or dorsalis pedis artery by the higher of the two brachial pressures. An ABPI of 0.9 is considered the lower limit of normal and values lower than this are indicative of PAD. Measures to increase the sensitivity and specificity of the ABPI for detection of PAD have been explored, including use of toe pressures, but at present it remains the best non-invasive test for PAD in terms of practicality, cost and accuracy. High sensitivity C-reactive protein and more recently cystatin C measurements may provide further information on cardiovascular risk, but are not widely used as yet.

Management of Peripheral Arterial Disease

Unfortunately, the role of tight glycemic control in preventing progression of PAD in diabetics is less clear, although it is certain that prevention of microvascular complications will reduce the need for revascularization and amputation in this patient population.

Hypertension should be controlled according to current guidelines with an emphasis on inhibition of the renin-angiotensin-aldosterone system, which has shown to improve claudication symptoms. High cholesterol states should be managed with lipid-lowering agents to prevent progression of lower extremity atherosclerosis and to reduce the risk of adverse cardiovascular events.

The optimal management of PAD begins with aggressive management of cardiovascular risk factors. Hypertension, dyslipidemia, and diabetes elevate the risk of adverse cardiovascular events and have the added detriment of accelerating atherosclerotic disease in the peripheral vasculature. Control of these risk factors by dietary modification, physical activity, and medications is essential in preventing disease progression.

Management strategies for PAD can be classified into lifestyle modification, pharmacological treatment, and revascularization by either endovascular or surgical techniques (surgical). Although the benefits of each individual strategy on symptom improvement and limb salvage have not been clearly quantified, a combination of all strategies is likely to provide the best outcome.

Lifestyle Modifications

C-reactive protein (CRP) is a marker of inflammation and elevated levels are associated with an increased risk of cardiovascular events and mortality in patients with PAD. This observational cohort study evaluated whether a strategy of intensive statin therapy to lower levels of CRP would provide further benefit to PAD patients in reducing the risk of cardiovascular and limb events. The study included 247 patients with PAD and an LDL cholesterol level of <130mg/dL and randomized them to receive a standard dose of atorvastatin 10mg/day or intensive atorvastatin therapy at 80mg/day. In the intensive therapy group, atorvastatin was titrated to achieve an LDL level of <80mg/dL and CRP level <2mg/L. High sensitivity CRP was measured in all patients at 6-monthly intervals and the primary outcome was the time to the first cardiovascular event including myocardial infarction, stroke, and death. The study was prematurely terminated after a mean follow-up of 1.2 years due to meeting the primary endpoint. The primary outcome occurred in 13% of the standard therapy group compared to just 1% in the intensive therapy group. This represented a 92% relative reduction in risk and the authors concluded that intensive statin therapy to reduce CRP to <2mg/L provides beneficial effects in reducing the risk of adverse cardiovascular events in PAD patients. Given the safety and tolerable side effects of statin therapy, this strategy is recommended in PAD patients with a goal of reducing the LDL as well as the CRP level.

Abstract The ankle brachial index (ABI) is influenced by arterial stiffness more than by luminal narrowing. This study compared the ability of the ABI and the toe brachial index (TBI), a more specific marker for lower extremity arterial disease and less affected by arterial stiffness, in predicting mortality in hemodialysis patients. ABI and TBI were measured in 212 hemodialysis patients at baseline, and the patients were followed up for 3 years. In univariate analysis, both ABI and TBI were significant predictors of all-cause and cardiovascular mortality. However, in multivariate analysis, TBI was a significant independent predictor of all-cause and cardiovascular mortality, whereas ABI was not. The authors concluded that TBI is superior to ABI in predicting all-cause and cardiovascular mortality in hemodialysis patients. This study highlights the limitation of ABI in assessing PAD in certain clinical groups and TBI could be a useful adjunct in these patients to more accurately assess the risk of adverse cardiovascular events and mortality.

Medications

Although exercise and medication therapies have been shown to improve walking performance in PAD, the combination of both has the greatest effect. A recent trial demonstrated that cilostazol or walking exercise therapy alone improved walk distance, but the combination of both significantly improved maximal walking times.

Other pharmacologic options to improve walking performance in claudication include statins and angiotensin-converting enzyme (ACE) inhibitors. High-intensity statin therapy should be prescribed to all patients with PAD to reduce cardiovascular events and improve walking distances. ACE inhibitors are recommended for those with PAD and hypertension, as they have been shown to improve cardiovascular outcomes and increase walking time.

Cilostazol, a phosphodiesterase III inhibitor, has been shown to increase maximal and pain-free walking distances in patients with intermittent claudication. It is the only medication therapy specifically approved by the FDA for the treatment of intermittent claudication and is recommended as an option to improve symptoms and functional status in patients with PAD.

Antiplatelet therapy is the cornerstone of medical therapy, as patients with PAD are at very high risk for cardiovascular events. Aspirin is recommended for all patients with PAD and clopidogrel should be considered for those with symptomatic PAD in the absence of other contraindications.

Guideline 1: Informative tone. Medication therapy is a valuable treatment option for patients with PAD and should be considered an important step in the overall treatment plan. Pharmacologic treatment of PAD centers around reducing cardiovascular risk and improving walking distance. In addition, prescription of medications to relieve leg symptoms or to improve walking performance is recommended.

Endovascular Interventions

Stent is a technique in which a scaffolding device is inserted into the vessel to prevent acute closure and late recoil. Stent may be primary (deployed after lesion preparation) or may be used as a bailout technique to treat acute vessel closure. A recent randomized trial comparing primary stenting with balloon angioplasty has shown that primary stenting is more effective for the treatment of iliac stenosis and was associated with fewer complications. Another trial has shown that primary stenting is also superior to angioplasty in the popliteal artery. There are various types of stents, including bare metal and covered stents, with drug-eluting stents being evaluated in randomized trials.

Atherectomy is a technique in which atheroma is excised from the vessel by a cutting or drilling device. Ideal lesions for atherectomy are long calcified stenosis. There are various types of atherectomy devices, including directional, rotational, and laser. A recent study comparing atherectomy and angioplasty for SFA stenosis has shown that atherectomy may be more efficacious in preventing late restenosis.

Balloon angioplasty is a technique in which a balloon is inflated within a vessel to eliminate the stenosis. The ideal lesion for angioplasty is short, not involving the common or external iliac artery, and not involving the popliteal artery. Complications of angioplasty include acute vessel closure and late restenosis.

Endovascular interventions are techniques and procedures in which a catheter is introduced into a vessel distant from the point of treatment. It is a relatively minimally invasive procedure that is indicated for patients with iliac and femoral disease, but also offers promise for the treatment of patients with below the knee disease. There are various procedures in the spectrum of endovascular interventions: balloon angioplasty, atherectomy, and stent.

Surgical Interventions

The mainstay of treatment for patients with severe peripheral arterial disease is revascularization through either bypass surgery or, less commonly, specific endarterectomy. Bypass surgery, similar to that done for coronary arterial disease, uses an autogenous vein to bypass areas of flow-limiting stenosis. The femoral popliteal artery is the most frequent site of surgery; however, the aortoiliac and more distal arteries can also be treated with favorable results. The decision to operate on a particular arterial segment depends on the likelihood of symptom improvement, the potential for delayed amputation, and the risk of producing concomitant ischemia in a previously well-perfused limb. Aortoiliac disease is generally associated with better results and higher rates of symptom improvement compared to femoral popliteal disease. However, aortofemoral bypass in the presence of coexistent femoral disease is still often beneficial. Patients with limb-threatening ischemia and poor potential for vein grafts can be considered for prosthetic grafts or aortoiliac revascularization via aortoiliac-femoral endarterectomy. Due to the minimally invasive nature and quick recovery time associated with endovascular interventions, surgery is less frequently performed in patients with comorbid conditions and poor life expectancy. However, surgery still offers the best chance of durable symptom relief and limb salvage for most patients with peripheral arterial disease.

Future Directions and Research

An area where evidence is scarce but conflicting, and the need for more research is highlighted, is in the management of intermittent claudication (IC). Although supervised exercise programs have been shown to bring about clinically significant improvements in pain-free and maximum walking distances compared to a control, this evidence is not matched for unsupervised exercise. This is a problem given that NICE guideline CG147 states that a patient should only be considered for revascularization if their symptoms are having a significantly negative impact on their quality of life. Therefore, a cost-effective self-management program which is simple enough to implement at a primary-care level would be preferable. Massage therapy is one such therapy which has been proposed for IC management, but evidence is mixed and inconclusive. A RCT involving 68 patients with mild to moderate IC found that massage therapy was effective in improving the 6-minute walking time and decreasing the visual analogue scale for pain compared to sham light massage. However, this did not correlate with increased maximal treadmill walking times and was not a long-term study. Massage therapy is based on the idea that it can improve circulation, reduce muscle ischemia, enhance relaxation, and possibly stimulate angiogenesis. This is further supported by a Cochrane review which reported that the effect of decongestive therapies (to which massage forms part of) on lymphedema, which can be considered a severe form of peripheral edema, were successful. More research elucidating the exact physiological effects and long-term benefits of massage therapy in IC would help determine it as a viable self-management strategy.

Although management of PAD has been well researched and understood, there are new fundamental mechanisms still being discovered which may well shape the future of treatment for these patients. One such discovery concerns the role of the inorganic molecule asymmetrical dimethylarginine (ADMA), which normally is broken down by dimethylargininase (DDAH) to its derivatives citrulline and dimethylamine. Raised levels of ADMA and reduced activity of DDAH have been noted in patients with PAD compared with age-matched healthy controls. This is important since ADMA is an endogenous inhibitor of nitric oxide (NO) synthesis by competing with L-arginine as a substrate for NO synthase (NOS). NO is known to play a crucial role in maintaining healthy endothelium and promoting vascular homeostasis by inhibiting platelet adhesion, smooth muscle proliferation, and inflammation. Therefore, the discovery of the ADMA pathway may help highlight a more specific target for treatment to maintain the protective effects of NO on the vascular wall. This pathway could, in theory, be manipulated using exogenous NO donors to flood the vessel wall with NO and overcome the inhibitory effects of ADMA. Alternatively, ADMA levels could be reduced, thereby increasing the bioavailability of NO using agents which modify its metabolism or increase DDAH enzyme activity. Studies into this and many other pathways associated with increased cardiovascular risk in PAD patients, such as inflammation, homocysteine, and oxidative stress, may act as a stimulus to develop newer, more advanced therapies specifically targeting these pathways compared with the use of antiplatelets and statins.

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