Peripheral Arterial Disease: Exploring the Role of Inflammation

The major cause of peripheral arterial infection is atherosclerosis. The factor that increases the risk of PAD is diabetes, a major cause of chronicity. Treating the PAD patient is important because PAD has a major impact on the patient’s health and functional status. However, the high rate of re-occlusion is causing unsatisfactory treatment results. Recently, endovascular recanalization with self-expandable nitinol stent-grafts has shown several advantages in treating superficial femoral artery and proximal deep femoral artery diseases. High primary patency rates ranging from 83-100% can be seen, including immediate opening, prevention of acute thrombosis, and no distal embolization. SFA is the common site of PAD, and difficult SFA lesions can be treated with a stent graft. The stent graft causes less vessel dissection and creates a smoother lumen compared to PTA. Currently, a new stent graft called VIABAHN ENDOGRAFT has been developed for the treatment of PAD on SFA and PFA. The BETAPAD register is evaluating the patency of VIABAHN on FP disease.

Understanding Peripheral Arterial Disease (PAD)

In the early part of the 20th century, it was held that the primary cause of atherosclerosis was a disorder of lipid metabolism. Our understanding of atherogenesis has since evolved, and it is clear that inflammation and immunity are playing a major role in this process. This concept first began to gather momentum with the observation of inflammation within the arterial intima at the earliest stages of atherosclerosis. Intimal thickening is known to occur at sites of haemodynamic stress, e.g. arterial branching, and is also the site where atherosclerotic lesions consisting mainly of cholesterol, cellular debris, and calcium begin to appear. It is now known that the evolution of the atherosclerotic plaque begins in response to injury to the endothelial lining of the artery. Endothelial cell dysfunction, e.g. increased permeability to lipids and expression of adhesion molecules, leads to abnormal subendothelial retention of lipoproteins. This, in turn, promotes the inflammatory process with leukocyte migration and the transformation of the retained lipids to oxidized low-density lipoproteins (LDL). The response of macrophages to these oxidized lipids in the artery is the ingestion to form ‘foam cells,’ and it is they that continue the cycle of inflammation and cell recruitment by releasing chemoattractants and growth factors. The above sequence of events has been mainly elucidated by studying Coronary Artery Disease (CAD), and there is now much evidence that similar processes are occurring in PAD.

Risk Factors

An association between diabetes and PAD has been noted, with diabetics having a two to four-fold increase in risk for PAD.

Despite progress in educating the public, tobacco use and smoking remain a large problem. Pattern or heavy tobacco use is the single greatest risk factor for PAD. Individuals who smoke or have a history of smoking have a two to ten-fold increase in risk for PAD. This is because tobacco decreases the amount of oxygen in the blood and damages the lining of the blood vessels. It also increases the buildup of plaque in the arteries and causes arteries to narrow. Fortunately, the risk for PAD for people who smoke, as well as their rate of mortality from the disease, decreases after smoking cessation.

High blood pressure is a significant risk factor for the development of PAD. High blood pressure is usually defined as a reading of 140/90 or higher. High blood pressure contributes to atherosclerosis and increases the workload on the heart. High blood cholesterol is yet another risk factor for PAD because it contributes to the buildup of plaque in the arteries. People with PAD are also at risk for developing renal artery disease caused by a decrease in blood flow to the renal arteries, eventually resulting in high blood pressure. High cholesterol is often managed and controlled with medication and a low-fat diet. This can also help to manage and control patients who have PAD or those who are at risk for its development.

Non-modifiable risk factors include age and family history. PAD is more common in older people, especially those over age 50. About one in every 20 people over the age of 50 has PAD. The risk of PAD increases as age increases. Having a family history of PAD, heart disease, or stroke also increases risk. If a person has one or more relatives with any of these conditions, especially before age 50, they are at increased risk for PAD. This is believed to be due to genetics as well as the environment in which they were raised. People of African descent are also at increased risk for PAD and its complications, with an increased rate of diabetes or hypertension being a likely factor. Although race itself is not a risk factor, it is likely that the prevalent risk factors for PAD among African Americans contribute to their increased risk. These risk factors are often associated with modifiable lifestyle risks which can contribute to their higher risk for developing PAD.

PAD risk factors can be categorized as non-modifiable or modifiable. Non-modifiable risk factors are those that you cannot change or control. Modifiable risk factors are those that have been proven to increase one’s risk of developing PAD and can be modified to decrease risk. Because the presence of both non-modifiable and modifiable risk factors increases the chance of developing PAD, it is important for people with any of these risk factors to control those that can be modified.


Claudication is a classic symptom of intermittent arterial claudication. It is usually, but not always, a constricting discomfort in the muscles that occurs during exercise and is relieved by rest. It is an inconsistent symptom and patients often modify their behavior to avoid the type of exercise that precipitates claudication. The location of the discomfort depends on the site of the arterial lesion. Calf pain is the most common location and is often bilateral. Thigh pain suggests iliac disease. Claudication of the buttock is less specific, occurring also in spinal and hip joint disease, and is more difficult to discriminate from neurogenic claudication. Claudication distance and the speed at which it develops are variable, and do not correlate closely with the severity of artery obliteration. Some patients have continuous rather than intermittent ischemic pain, and in severe limb ischemia the pain may occur at rest, disturbing sleep and causing the patient to dangle the limb over the edge of the bed to obtain relief by gravity dependent flow. A few patients with extensive arterial disease may have no pain symptoms, but present with ulcers or gangrene of the feet. Temperature and color change of the feet and toes may occur in patients with severe limb ischemia and are sometimes the presenting symptoms. An ischemic ulcer is usually painful and is an important landmark in the natural history of PAD. RP is a common condition, the etiology of which is often uncertain. An important cause is atherosclerosis, but it may be the presenting feature of systemic vasculitis and it occurs also in association with other connective tissue diseases. In its classical form it consists of episodic discoloration of the digits on exposure to cold, followed by a characteristic triphasic color sequence white (pallor), blue (cyanosis) and red, accompanied by pain. This is the result of an exaggerated vasoconstriction response to ambient temperature change, due to abnormal neuro-vascular control. The condition is often unreported by patients and is a frequent incidental finding in clinical examination.


Currently, the most effective diagnostic tools for PAD are non-invasive physiological tests. Measurement of the ankle-brachial index (ABI) is the most cost-effective tool for diagnosis of PAD. The ABI compares the blood pressure in the arm to the blood pressure in the leg to determine how well blood is flowing. An abnormal ABI is a strong indicator of PAD and is anything less than 0.90. An ABI of 0.90-0.99 is borderline and anything greater than 1.4 is also indicative of PAD. The ABI has a sensitivity of 90% and a specificity of 95% for detecting PAD, making the ABI a simple, yet valuable tool in diagnosing PAD. Pulse volume recordings and segmental blood pressure measurements may also be used in addition to ABI for diagnosis as well as determine the severity and location of the disease.

The diagnosis of PAD is critical to providing the best treatment for the patient, especially if the disease is still in the asymptomatic stages. Despite its relatively high prevalence, only a minority of patients with PAD are actually diagnosed by a physician. Physicians can too easily pass off leg symptoms of fatigue and cramping as a normal part of aging. Patients may also dismiss their leg symptoms as signs of aging. Finally, even when PAD is suspected, other diseases such as arthritis can often confound the diagnosis. Therefore, active assessment for PAD is essential for accurate diagnosis.

Inflammation and Its Connection to PAD

The immune and inflammatory responses enhance atherosclerosis and produce effects on systemic and vascular functions that can result in clinical complications of atherosclerosis. High sensitivity C-reactive protein (hsCRP), a systemic marker of inflammation, is a notable risk marker in atherosclerosis and PAD.

Immune and inflammatory responses also have effects on lipoprotein metabolism and affect the structure and function of lesion components in a beneficial or detrimental way, either stabilizing or further progressing lesions to a vulnerable state. A large body of evidence supports the concept that inflammation in atherosclerosis is an autoimmune-like response to oxidized LDL, with both cellular and humoral immune responses being specific to oxidized LDL epitopes.

Numerous cytokines and growth factors are expressed in atherosclerotic lesions by macrophages, T cells, and some by smooth muscle cells. These include interleukin-1, interleukin-12, interleukin-18, tumor necrosis factor, and type 1 interferons, which promote a pro-inflammatory environment. Inflammatory chemokines are important in adhering immune cells to activated endothelium and migration of these cells into the artery wall.

The immune and inflammatory systems are important in the pathogenesis of atherosclerosis. Immune responses take place in a milieu of inflammation containing a balance of pro-inflammatory and inflammatory mechanisms. Though the causes of initiation of immune and inflammatory responses in atherosclerosis are not entirely clear, it is recognized that modified lipoproteins within the arterial intima are a key factor. High levels of cholesterol can lead to an accumulation of lipids in the artery wall. Modified lipoproteins, e.g. oxidized LDL and small dense LDL, are taken up by macrophages and smooth muscle cells to form foam cells. Foam cells are the hallmark of the fatty streak of atherosclerosis.

Inflammatory processes in arteries are now known to play a critical role in the development of atherosclerosis and its clinical manifestations, particularly in coronary and peripheral arterial disease (PAD). Inflammation participates in all phases of atherosclerosis, from the initiation and growth of atherosclerotic lesions to the thrombotic complications of atherosclerosis.

Inflammatory Processes in Arteries

Inflammatory processes in arteries encompass two major pathways, one initiated by lipids (mainly oxidized LDL) and another initiated by risk factors such as hypertension or shear stress. Both pathways converge on the inflammatory cytokine tumor necrosis factor alpha (TNF), the master regulator of inflammation. A central downstream effect of TNF is induction of IκB, which is a negative regulator of adhesion molecule induction. This prevents the second wave of inflammation, thus in the presence of IκB degradation, the induction of adhesion molecules is unopposed. At the site of inflammation, leukocytes bind to the adhesion molecules expressed on endothelium and then migrate into the intima. Smooth muscle cells, normally residing in the media, also migrate into the intima in response to inflammatory signals. The accumulating LDL and the invading leukocytes are internalized by macrophages, converting them into foam cells, the hallmark cell of early atherosclerotic lesions. Smooth muscle cells, macrophages and T lymphocytes secrete various enzymes and growth factors that cause further injury to the arterial wall and create a prothrombotic state. If commenced early enough in lesion development, this entire process can be prevented by the absence of ApoE or by infusion of a statin.

Role of Inflammation in PAD Development

Inflammatory cells are a ubiquitous feature of early atherosclerotic lesions, where they are found in close association with macrophages. Although they were formerly believed to play only subversive roles in the atherosclerotic process, it is now recognized that inflammation and immunological processes are major participants in the causation and propagation of lesions. This new understanding was born from findings that raised systemic markers of inflammation, such as C-reactive protein, are strong predictors of future cardiovascular events. Similarly, a number of pro-inflammatory states, including rheumatological conditions and certain infections, have been shown to accelerate atherosclerosis. Investigations into how inflammation promotes atherosclerosis have identified several paradigm-shifting concepts. One of these is that modified lipids and cholesterol crystals found within atherosclerotic plaque can serve as sources of antigens that trigger immune responses. This leads to a heightened recruitment of monocytes and other cells from the adaptive immune system to the atherosclerotic lesion, and a chronic immune response can cause damage to surrounding tissue. In addition to this, there is now evidence that inflammatory cytokines can increase hepatic synthesis of CRP and other acute phase reactants, which can become systemic contributors to atherosclerosis. These new developments have both pathophysiological and clinical implications for PAD.

Management and Treatment of PAD

As well as exercise therapy, cessation of smoking is essential in the management and prevention of progression of PAD. Smoking has been shown to have a dose-dependent effect on the incidence of intermittent claudication and may lead to a 4-fold increase in the risk of PAD requiring bypass surgery. Unfortunately, because smoking is such a potent risk factor, patients who continue to smoke following revascularization procedures have a high risk of symptom recurrence and re-occlusion of their vessel. An initial advice-giving approach to smoking cessation is often ineffective. Many PAD patients will require cessation interventions such as group therapy or pharmacotherapy with the use of nicotine replacement therapy or antidepressant drugs. A review of one small pilot trial on the use of group therapy in PAD patients showed promise. At 12 months, the smoking cessation rate was 22% in the treatment group, and this was associated with a significantly improved claudication onset time.

4.1 Lifestyle Modifications Physical activity can improve symptoms and functional status in PAD patients. Despite initial worsening of symptoms due to the change in level walking ability, participation in a supervised exercise program has been shown to increase pain-free walking time as well as overall walking ability. Exercise therapy has been shown to be equally effective in alleviating symptoms and improving walking performance in lower extremity PAD when compared with revascularization procedures. The presence of significant comorbidities does not preclude the use of exercise therapy in PAD patients. It has been shown that following cardiovascular risk assessment, and providing comorbidities are stable, supervised exercise training is safe, even in individuals with moderate to severe cardiovascular disease.

The foundation for PAD management is cholesterol and blood pressure control. Lifestyle risk reduction of tobacco exposure and physical activity are the cornerstones of all programs. The goals are to improve symptoms, prevent progression of disease, and to decrease cardiovascular events risk. In every PAD patient, we advocate aggressive and global atherothrombotic risk factor reduction with the use of a statin and a combination of anti-platelet and anti-coagulant therapy.

Lifestyle Modifications

Several studies have identified significant associations between patients with PAD who adhere to an exercise programme and improvements in their physical functioning. Many of these findings are drawn from supervised exercise interventions, the benefits of which appear to be more consistent than those of home-based exercise. Unfortunately, the benefits of exercise are lost within about 2-4 weeks of ceasing exercise, and as such, exercise is an effective yet costly form of therapy for the patient with intermittent claudication, maintaining a role provided that improved functioning and cardiovascular health and longevity are determined to be priorities for the individual patient. Nonetheless, it should be reinforced to all patients with PAD that simply increasing daily walking duration in itself may be beneficial. In particular, gait speed is significantly associated with lower extremity functioning and mortality in PAD patients. Attempts to increase walking duration may result in increased walking distance over time, as individual sessions of uninterrupted walking may extend. Although intermittent claudication may lead to the preservation of energy by way of isolating lower extremity activities, it is likely that for any given period that a patient is on his/her feet, the slower his/her walking speed, the less distance will be covered. An increased daily walking duration and speed may be accomplished with minimal initial disruption to current activities of daily living with the aid of a supervised walking programme and/or the use of pharmacologic therapies. The goal of any exercise programme should be to increase daily walking duration and distance in such a manner that does not result in severe pain and/or sustained muscle ischaemia.


Cilostazol is a phosphodiesterase III inhibitor which increases intracellular cyclic adenosine monophosphate (cAMP) and inhibits platelet aggregation. High cAMP levels reduce intraplatelet calcium concentrations and down-regulate expression of platelet GPIIb-IIIa receptor, leading to a reduction in platelet activation and aggregation. Cilostazol has complex effects on haemostasis and the coagulation system. In addition to inhibition of platelet function, it has vasodilatory effects and increases red blood cell flexibility, which may improve microcirculatory flow. An early randomized controlled trial reported benefit from cilostazol in improving peripheral symptoms and increasing pain-free walking distance. This was followed by two large double-blind placebo-controlled multicenter trials, the Cilostazol for Restenosis After Femoropopliteal Angioplasty to Lower Restenosis (CREST) and Cilostazol in the Management of Atherosclerotic Obstructive Peripheral Arterial Disease (CAPRIE) trials.

Statins reduce LDL cholesterol by inhibiting HMG-CoA reductase. The resulting fall in hepatic intracellular cholesterol leads to an up-regulation of hepatic LDL receptors and increased clearance of LDL cholesterol from the blood. This is a key mechanism by which statins reduce cardiovascular events and mortality, particularly in patients with established cardio- or cerebrovascular disease. The influence of statins on atherosclerotic plaque burden has been investigated by several methods. In a substudy of the Post Coronary Artery Bypass Graft Trial, atorvastatin therapy was associated with a reduction in atheroma volume as assessed by intravascular ultrasound (IVUS) which was correlated with reductions in LDL cholesterol. Similar findings have been reported for simvastatin and pravastatin. More recently, the Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin (METEOR) study demonstrated a reduction in carotid artery intima-medial thickness progression in patients treated with rosuvastatin compared with placebo, using carotid ultrasound. High-dose (80mg) atorvastatin therapy was associated with regression of coronary atherosclerosis over 2 years as assessed by IVUS in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Benefit from statin therapy has been demonstrated in patients with PAD in the Heart Protection Study and the subgroup of patients with PAD in the Treating to New Targets (TNT) trial where reductions in major cardiovascular events in patients treated with atorvastatin were unaffected by the presence of PAD.

Surgical Interventions

Patients treated with stents had significantly better walking distances and less procedural morbidity; however, there was no difference in the primary endpoint between the treatment groups. Open surgery in the form of bypass grafting appeared to yield favorable outcomes when compared to endovascular treatment for critical limb ischemia, especially in the case where vein was used as a conduit. However, a study comparing endovascular treatment and bypass surgery using the angioplasty and stenting for occluded vein grafts III trial showed that bypass surgery was superior for infrainguinal lesions, especially in those with the presence of claudication. In both cases, the two surgical methods have their relative strengths and weaknesses, and a management plan should be made on a case-by-case basis.

Surgical management for PAD can be categorized into three main groups: endovascular, percutaneous, or open surgery. The purpose of surgery is to revascularize the affected limb, which may help reduce the incidence of amputation and death from cardiovascular disease. One group investigated patients with intermittent claudication and unilateral common femoral artery stenosis. 48 patients were randomized to receive either femoral endarterectomy or an aortoiliac stent, and the primary endpoint was improvement in walking distance after 12 months.

Inflammation-targeted Therapies

Several lines of evidence have shifted the paradigm of atherosclerosis and its correlated clinical syndromes away from cholesterol alone as the sole or key initiator for disease. Evidence regarding the oxidant hypothesis and role of immune response to modified LDL as a stimulant for a chronic and damaging inflammatory response by the vessel wall has been well developed. More so, recent trials have shown inflammation to be a viable and appealing target for the treatment of atherosclerosis and its clinical manifestations. This has come in the shape of inflammation-targeted therapies. One of the first avenues was the use of antioxidants such as vitamin E. Despite initial promise and the postulation that antioxidants in theory could retard atherosclerosis progression, these have largely been deemed unsuccessful with no clear benefit on clinical outcome. The somewhat failure of such therapies was concurrent with the production of data showing the competitive inhibition of the pro-inflammatory transcription factor NFkB to produce a reduction in atherosclerosis lesion development and less advanced lesions in animal models. This was then followed by several human trials with agents such as monoclonal antibodies against cell adhesion molecules. Yet, the breakout into inflammation-targeted therapy only truly occurred with the use of statins. The HMG-CoA reductase inhibitors, more known for their profound effects on reducing LDL cholesterol and its associated clinical benefit particularly in the field of coronary artery disease, have a class effect in also downregulating other mechanisms that fuel the inflammatory process and thus prove to have a benefit on atherosclerosis lesion progression and clinical events beyond that which would be expected from LDL reduction alone. For example, in the TNT trial, 10 mg of atorvastatin daily produced regression of atherosclerosis in coronary vessels as demonstrated by intravascular ultrasound. This has prompted further trials in the reversing atherosclerosis by aggressive cholesterol lowering (REVERSAL) study, which demonstrated that intensive lipid lowering with atorvastatin, as compared with pravastatin (an effect which dynamically reduces CRP), could lead to the regression of atherosclerosis in the carotid artery.

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