Pathophysiology of Peripheral Artery Disease

Functional Limitation and Cardiovascular Risk

Patients with PAD develop limb symptoms that impair walking ability. The classic clinical manifestation of PAD is intermittent claudication, characterized by leg discomfort with activity that resolves with rest (see Chapter 18 ). The term claudication is derived from the Latin word claudicato , meaning “to limp,” which is typical of the gait pattern of the patient who experiences limb ischemia when walking. Patients describe leg cramping, heaviness, or fatigue in the muscles of the buttock, thigh, or calf, which comes on exclusively with exercise, escalates with increasing activity, and diminishes rapidly with rest. This sequence of exercise-induced progression and complete relief with rest are important clinical differentiators of claudication from other lower-extremity musculoskeletal conditions. The pain is not positional or precipitated by standing alone. Typical intermittent claudication is present in only 10% to 20% of patients with PAD defined by ABI. A much larger group of PAD patients experience atypical leg symptoms, leading to reduced walking capacity. Impaired functional ability is present in PAD patients regardless of symptom category, and asymptomatic patients with PAD are at risk for progressive functional impairment. Compared to healthy individuals of the same age, patients with claudication have a marked reduction in peak treadmill performance. There are multiple contributing factors driving exercise limitations in PAD, including self-restriction of activity to minimize leg pain.

Functional limitations in patients with PAD leads to poor clinical outcomes. Several studies demonstrate that these patients have reduced quality of life related to leg pain and activity restriction. Reduced walking ability measured by questionnaires or direct assessment is associated with higher cardiovascular events, limb events, and mortality. ^, Longitudinal declines in exercise performance predict mortality risk in PAD, and lower physical function predicts decline in ABI. ^, Thus, a key therapeutic goal in PAD is preservation and restoration of walking ability.

In addition to limb manifestations, patients with PAD have high rates of cardiovascular events (see Chapter 16 ). In clinical registries, more than half of PAD patients have coexistence of clinical coronary artery disease and/or cerebrovascular disease. PAD predicts a high risk for cardiovascular events regardless of symptom status. Patients with polyvascular disease, in which atherosclerosis is manifest in multiple territories, have particularly poor outcomes. Thus treatment to reduce atherosclerotic risk is a key component of PAD treatment (see Chapter 19 ).

Chronic and Acute Limb Threatening Ischemia

CLI is critically severe arterial insufficiency leading to inadequate tissue perfusion at rest. CLI is defined by rest pain in the leg for more than 2 weeks and/or the presence of nonhealing wounds or gangrene in the presence of arterial obstructive disease. ALI is the rapid onset of severe ischemia of less than 2 weeks’ duration and the classic clinical signs of pallor, pulselessness, coolness (poikilothermia), paresthesia, and paralysis (see Chapter 44 ). A key outcome in symptomatic PAD is the occurrence of major adverse limb events (MALE) defined as amputation, CLI, or ALI. In the overall adult US population, the annual incidence of CLI is estimated at 0.2% to 0.4% in an analysis of recent administrative datasets, with a prevalence of 0.23% to 1.33%. In analyses based on insurance claims data, out of the total number of patients diagnosed with PAD, 11% had prevalent CLI. Patients with CLI have poor limb-related outcomes, including 35% to 67% amputation rates, and mortality rates as high as 40%, particularly in patients with tissue loss. CLI patients typically have arterial obstructions in multiple segments, which usually involve the infrainguinal and tibial vessels. The arterial stenoses and occlusions reduce limb perfusion, and limit oxygen and nutrient supply to an extent that produces resting ischemia and progresses to tissue compromise. ALI occurs when there is an abrupt reduction in limb blood flow related to thrombosis or embolism. The overall incidence of ALI is low, approximating 1.5 cases per 10,000 person-years. In clinical trials, the annual rate of ALI is 1.3% in established PAD patients, with higher rates in patients with prior peripheral revascularization and in patients who continue to smoke. Rates of amputation and recurrent limb events remain high following ALI. Revascularization for limb preservation is crucial in both ALI and CLI.

Arterial Flow and Oxygen Delivery to Skeletal Muscle

Muscle oxygen consumption involves oxygen delivery (mediated by pulmonary oxygen uptake, oxygen content of hemoglobin, and blood flow) and oxygen extraction by the skeletal muscle. In healthy people, both at rest and during exercise, muscle oxygen consumption is determined primarily by maximal oxygen delivery. Muscle oxidative capacity, the amount of oxygen converted to energy by mitochondria, remains tightly coupled with maximal exercise capacity and increases with exercise training. Blood flow to skeletal muscle also increases with exercise and with exercise training.

Determinants of Limb Blood Flow

At any given systemic blood pressure, the major determinant of blood flow in regional circulations is the peripheral resistance of the vascular bed supplied by major conduit vessels. This basic relation can be expressed as:

Delivery of blood flow is matched to demand by adjustments in the arteriolar vascular resistance through vasoconstriction or vasodilation. In the healthy blood vessels without obstruction, exercise is a major stimulus for vasodilation, causing a decrease in peripheral resistance, which, when combined with an increase in arterial pressure, results in a large increase in limb arterial flow to supply sufficient oxygen to accommodate exercising muscular oxygen consumption. Normal arteries have the capacity to support large volumetric increases in blood flow without a significant drop in pressure across the large and medium conduit vessels ( Fig. 17.1 ).