Atherosclerosis of artery of both lower extremities

Abstract

Peripheral arterial disease (PAD) is a manifestation of atherosclerotic disease in the arteries to the legs. The clinical presentation of PAD includes a spectrum that spans individuals with asymptomatic disease, those who experience intermittent claudication (IC), and those with more severe symptoms of critical limb ischemia. PAD is a common condition that affects a large proportion of the adult population worldwide. The estimated prevalence of claudication ranges from 0.4% to 14.4%. The prevalence of asymptomatic disease diagnosed with noninvasive tests is much higher and ranges between 0.9% and 22% with the ratio of symptomatic to asymptomatic ranging between 1:0.9 and 1:6. Risk factors for atherosclerosis such as age, cigarette smoking, diabetes, dyslipidemia, and hypertension increase the likelihood of developing lower extremity PAD. The majority of patients with IC experience stabilization of their symptoms within 5 years and only 10–15% ever develop critical limb ischemia. Both claudicants and those with asymptomatic disease are at increased risk of systemic cardiovascular events.

Arteriosclerosis Obliterans

Arteriosclerosis obliterans (atherosclerotic occlusive disease, chronic occlusive arterial disease, obliterative arteriosclerosis) is the peripheral arterial presentation of atherosclerosis. Most often, arteriosclerosis obliterans affects the lower abdominal aorta, the iliac arteries, and the arteries supplying the lower extremities. Upper extremity manifestations are rare.

Arteriosclerosis obliterans is responsible for 95% of cases of chronic occlusive arterial disease. It is most common in persons older than 50 years, but as many as 19% of cases occur in patients 30 to 49 years old. Men are affected more often than women (5 : 1 to 10 : 1). Approximately one-third of patients with arteriosclerosis obliterans have coexistent coronary artery disease. The incidence of diabetes mellitus is 20% to 30%.19

Risk factors for arteriosclerosis obliterans include cigarette smoking, hyperlipidemia, and hypertension. Of patients with arteriosclerosis obliterans, 70% to 90% are smokers when first examined, 75% have hyperlipidemia, and 30% have hypertension.19

Epidemiology and Risk Factors for Peripheral Arterial Disease

Peripheral arterial disease is characterized by obstruction in arterial beds other than the coronary arteries and is caused by atherosclerosis in the vast majority of patients. The most common site is the lower extremity, where occlusive disease leads to impaired perfusion. The major established risk factors for the development of PAD are essentially the same as those recognized as important in generalized atherosclerosis, and include increasing age after 40 years, cigarette smoking, diabetes mellitus, hyperlipidemia and hypertension (Table 53.1) (Fowkes, 1990; Hiatt et al., 1995). Elevated levels of C-reactive protein and homocysteine may also be important risk factors (Darius et al., 2003; Gerhard et al., 1995; Graham et al., 1997).

Table 53.1. Epidemiology, risk factors and clinical manifestations of peripheral arterial disease

Intermittent claudicationCritical limb ischemiaRisk factorsDiabetesKnown risk factorKnown risk factorSmokingKnown risk factorKnown risk factorHypertensionKnown risk factorKnown risk factorHyperlipidemiaKnown risk factorKnown risk factorC-reactive proteinKnown risk factorKnown risk factorClinical characteristicsPain with ambulationUsually presentUsually presentPain at restUsually not presentUsually presentUlceration or gangreneUsually not presentMay be presentABI <0.9Usually presentSometimes associated with lower ABIs, but low ABI does not predict diseaseAnnual mortality1–2%20%Amputation rate1–2%25–40%Biochemical characteristicsB2 microglobulinHigher levels in PAD patients, but not shown to differentiate between IC and CLI*Angiogenic factors or receptorsHigher levels of sTie 2† in PAD patients, and also shown to differentiate between IC and CLI‡

ABI, ankle-brachial index; IC, intermittent claudication; CLI, chronic limb ischemia.

Although previously under-recognized and under-diagnosed by the medical community and therefore viewed as less important than heart disease, PAD is now recognized to have a prevalence similar to that of ischemic heart disease (Gerhard et al., 1995; Kannel and McGee, 1985). It affects about 3–10% of adults in the world and 15–20% of those over 70 years, suggesting an increased prevalence with age, and with an aging population one would expect that the prevalence of PAD will continue to increase (Hirsch et al., 2001; Norgren et al., 2007).

PREVALENCE AND IMPACT

Peripheral arterial disease (PAD) is a chronic occlusive disease that limits blood flow of the arterial circulation to the lower extremities caused by atherosclerosis. The disease may be asymptomatic at first, then it may progress to intermittent claudication, and eventually to severe ischemia in some cases. Although more than 50% of those with PAD are asymptomatic, those with symptoms usually exhibit lower-extremity pain only with exercise (intermittent claudication). Signs and symptoms of severe ischemia include pain at rest, ulceration, and gangrene. This clinical presentation is related to the degree of ischemia, which causes a reduction in blood flow to skeletal muscle, tissue, and skin of the affected area.

The prevalence of PAD increases with age. In several epidemiologic studies, prevalence of PAD ranged from 13% to 32% in individuals 80 years of age.1

Introduction

Peripheral arterial disease affects 13% to 14% of the elderly (>65 and older) population and thus affects more than 27 million in the United States and Europe [1]. Chronic peripheral ischemia commonly presents as intermittent claudication, which can progress to ischemic rest pain, and to ulcers and gangrene that may ultimately lead to amputation. Lower limb amputation implies a poor prognosis, with a recent study showing 44% and 77% of these patients dying within one and five years post-amputation, respectively [2]. Despite the poor prognosis, only half of PAD patients are candidates for the current standard of care endovascular therapies. The remaining population are ineligible due to complex anatomies and/or co-morbidities [3,4]. Those patients with critical limb ischemia that are able to receive endovascular therapies remain at risk for amputation with a 5-year amputation-free survival rate of only 35%.

Our knowledge of cells, extracellular factors and signaling pathways orchestrating angiogenesis, arteriogenesis and vasculogenesis has greatly advanced since the first report describing angiogenesis in 1971 [5]. Early studies of angiogenic factor treatment yielded promising pre-clinical studies, which led to the investigation of cell therapies and angiogenic factors for peripheral arterial disease (PAD) in the clinical setting for the past two decades [6]. Though early trials have provided evidence for clinical safety and bioactivity, a positive Phase 3 pivotal trial has yet to be conducted in the field. This chapter describes the clinical findings of cell therapy and angiogenic factors for the treatment of peripheral arterial disease, and discusses new approaches and insights into effective modulation of vascular response to ischemia for the treatment of peripheral artery disease.

Introduction

Peripheral arterial disease (PAD) of the lower extremities is one of the major manifestations of systemic atherosclerosis. The disease affects from 4% to 12% of adults (depending on the population studied).1,2 Risk factors are typical of those for atherosclerosis and include advanced age, cigarette smoking, diabetes mellitus, hyperlipidemia, hypertension, and inflammation; the most important are diabetes and smoking.1,3

Clinical manifestations of PAD range from asymptomatic in 20% to 50%, atypical leg pain in 40% to 50%, typical claudication in 10% to 35% and critical leg ischemia (CLI) in 1% to 2% (Fig. 22‐1). Asymptomatic patients with PAD have severely limited limb function, including limited walking distance and speed.4 Therefore, from a functional perspective, all patients with PAD have symptomatic limitations.

Claudication is pain in the legs on walking, primarily in the calves, which does not go away with continued walking and is relieved by rest. Among patients with claudication, symptom severity follows a stable course over 5 years in 70% to 80%, with only 10% to 20% developing worsening claudication and 1% to 2% experiencing the onset of CLI, which is the most severe manifestation of PAD.5 Patients with CLI have severe arterial occlusive disease, usually involving multiple segments. Clinical evidence of CLI includes ischemic pain in the distal foot, ischemic ulceration, or gangrene. Patients with CLI are at high risk of limb loss.

PAD is highly associated with critical coronary and carotid artery diseases, and it predisposes patients with these conditions to markedly increased risks of myocardial infarction, ischemic stroke, and vascular death.6 For example, in patients with PAD, adjusted cardiovascular mortality is increased sixfold.7 This risk is approximately equal between men and women, and it is elevated even if the patient has had no prior clinical evidence of cardiovascular disease.8 With increasing severity of PAD, as measured by the ankle‐brachial index (ABI), come concomitant increased risks of myocardial infarction, ischemic stroke, and vascular death.9 After 5 years, 20% of patients experience a nonfatal myocardial infarction or stroke, and 15% to 30% die (see Fig. 22‐1). Therefore, the initial goals of management are to recommend changes in lifestyle, to identify and modify cardiovascular risk factors, and to administer antiplatelet drugs to reduce the risk of cardiovascular events. These treatments may also slow the progression of atherosclerosis in the peripheral circulation and may inhibit clinical progression of disease.

In patients with claudication, the goal of treatment is to improve exercise performance, community‐based walking ability, and quality of life. In patients with CLI, the goals of therapy are to prevent limb loss, to heal ischemic ulcers, to relieve pain at rest, and to improve functional status. For patients with claudication, approaches used to treat symptoms include supervised exercise rehabilitation, administration of cilostazol, and select use of revascularization procedures. In contrast, no effective medical therapy for CLI is available, as these patients require restoration of blood flow to heal wounds, relieve ischemic pain, and prevent limb loss.

Epidemiology

The prevalence of peripheral artery disease (PAD) as a reflection of systemic atherosclerosis is dramatically increasing with aging of the population. According to abnormal preliminary diagnostic tests such as the ankle-brachial index (ABI), the overall 3%–10% prevalence of PAD increases to 15%–20% in ages older than 70 years.1

The inflammatory nature and atherosclerotic basis of PAD pathology make this entity a mirror of increased risk of myocardial infarction (MI) and stroke in addition to impaired quality of life (QoL). The least important consequence of PAD underdiagnosis and undertreatment is the potential of developing critical limb ischemia (CLI). The risk of cardiovascular events, even in asymptomatic patients, increases three- to fourfold.2

The prevalence of PAD is similar between older men and postmenopausal women, but the classic symptoms of disease are more common among men, especially at a younger age.3 A higher incidence of symptomatic PAD in men mirrors their greater disease severity.4

Among common risk factors of PAD with other atherosclerotic diseases, smoking and diabetes are predominant and independent, but hypertension and dyslipidemia contribute less risk.5 It is worth pointing out that the leg amputation rate in diabetic patients is an indicator of health systems performance.6

Introduction

Herein, we define peripheral arterial disease (PAD) as significant obstructive atherosclerosis in the arterial system of the lower extremities. Representative clinical manifestations of PAD include intermittent claudication and tissue loss of the feet or toes. Both are typically due to the extensive accumulation of atherosclerotic plaques that lead to tissue ischemia and, in the case of tissue loss, necrosis. In some cases, arterial revascularization is performed to restore adequate oxygen supply distal to the obstruction.

How is atherosclerosis of the leg treated?

What is atherosclerosis of lower extremities?

What are the symptoms of atherosclerosis in the legs?

What is the most common site of atherosclerosis in the lower extremity?