Peripheral artery disease, or PAD, is a circulatory condition that results from the narrowing of arteries, which reduces blood flow to various parts of the body, most commonly the legs. Understanding the pathophysiology of PAD involves examining the biological sequence of events that leads to the development and progression of this condition. It is a process that unfolds over many years, often silently at first, before symptoms become apparent.
The Initial Trigger: Endothelial Dysfunction
The process of peripheral artery disease begins with damage to the inner lining of the arteries. Healthy arteries are lined by a thin layer of cells called the endothelium, which acts as a protective barrier and helps regulate blood flow smoothly. This delicate lining can be harmed by various factors, leading to a condition known as endothelial dysfunction, where it loses its ability to properly regulate the tone of the blood vessel and maintain a non-stick surface.
This initial damage is often a direct result of common health issues. Factors such as high blood pressure, elevated levels of blood sugar from diabetes, high cholesterol, and the chemicals from smoking are all known to cause injury to the endothelial cells. This damage to the endothelium is the first step that allows for the development of the blockages characteristic of PAD, setting the stage for the next phase of the disease.
The Inflammatory Cascade and Plaque Buildup
Following the initial damage to the endothelium, the compromised protective layer allows low-density lipoprotein (LDL) cholesterol, often referred to as “bad” cholesterol, to more easily enter the artery wall. This accumulation of LDL cholesterol within the subendothelial space triggers an inflammatory response from the body.
The body’s immune system recognizes the buildup of cholesterol as an abnormality and sends immune cells, specifically macrophages, to the site of injury. These macrophages attempt to clear the cholesterol by engulfing it, a process that transforms them into what are known as “foam cells.” These foam cells, along with smooth muscle cells that have migrated into the area and other cellular debris, begin to accumulate within the artery wall.
Over a long period, this collection of foam cells, smooth muscle cells, and other substances hardens into a structure called an atherosclerotic plaque. The growth of this plaque is a slow and gradual process that significantly narrows the artery.
Functional Impact of Reduced Blood Flow
The progressive buildup of atherosclerotic plaque has direct physical consequences on blood circulation. As the plaque grows, it narrows the interior of the artery, a condition known as stenosis, restricting the amount of blood that can flow through. When blood flow is reduced to a point where the tissue downstream does not receive enough oxygen, a state of ischemia occurs.
This reduction in oxygen-rich blood flow leads to the most common symptom of PAD, known as intermittent claudication. This symptom is characterized by pain, cramping, or aching in the leg muscles, such as the calves, thighs, or buttocks, that occurs during physical exertion like walking and is relieved by rest. During activity, muscles require more oxygen, but the narrowed arteries are unable to supply the increased demand, leading to ischemic pain.
The severity of the functional impairment often correlates with the degree of the blockage. Even in individuals who do not experience classic claudication, the reduced blood flow can lead to other symptoms such as muscle weakness, hair loss on the legs, and skin that is cool to the touch. Over time, this chronic lack of adequate blood flow can contribute to a decline in physical ability and overall mobility.
Disease Progression and Acute Events
In the more advanced stages of peripheral artery disease, the condition can progress beyond the stable narrowing of the arteries. The atherosclerotic plaques themselves can become unstable. The fibrous cap that covers the plaque can thin out and become prone to rupture, which can lead to more sudden and severe complications.
When a plaque ruptures, it exposes the contents of the plaque to the bloodstream, triggering the body’s natural clotting mechanism. This results in the formation of a thrombus, or blood clot, on the surface of the plaque. This blood clot can rapidly and severely obstruct the artery, leading to a sudden and critical reduction in blood flow known as acute limb ischemia, which is a medical emergency.
This process of plaque rupture and thrombosis is also a factor in the development of critical limb ischemia (CLI). CLI is a severe form of PAD characterized by pain even at rest, non-healing sores, or ulcers on the legs and feet. The formation of clots on top of existing plaques contributes to the progressive worsening of the disease and the potential for serious complications, including tissue death and the need for amputation.