Peripheral artery disease (PAD) is usually caused by atherosclerosis, a progressive process in which fatty material, cholesterol, cellular debris and other substances accumulate within the walls of arteries. In PAD, this process most commonly affects arteries supplying the legs, reducing the internal diameter of the vessels and restricting the amount of oxygen-rich blood that can reach muscles and other tissues.
Atherosclerosis develops through injury and dysfunction of the arterial lining, followed by inflammation, accumulation of lipids within the arterial wall, formation of atherosclerotic plaque and, over time, changes such as fibrosis and calcification. The narrowing may develop gradually, allowing the body to establish collateral blood vessels that partly compensate for reduced flow. PAD is therefore generally a manifestation of systemic arterial disease rather than an isolated problem confined to one leg.
Smoking is one of the most important modifiable causes and risk factors for PAD. Tobacco smoke exposes blood vessels to chemicals that promote endothelial dysfunction, inflammation, oxidative stress, abnormal platelet activity and progression of atherosclerotic plaque. Smoking also causes vasoconstriction and reduces oxygen delivery, potentially making the functional consequences of arterial narrowing more pronounced. The relationship is dose-related in general: greater exposure and longer duration of smoking are associated with greater vascular risk. Stopping smoking reduces ongoing vascular injury and is a major component of PAD management because the disease reflects the same systemic atherosclerotic process that can affect the coronary and cerebral arteries. NHS guidance identifies smoking as the most significant risk factor for PAD.
Diabetes mellitus substantially increases the risk of PAD because chronically elevated blood glucose can damage the vascular endothelium, alter inflammatory pathways and accelerate atherosclerotic disease. Diabetes also affects nerves and small blood vessels, which can complicate the recognition and consequences of reduced arterial circulation. Both type 1 and type 2 diabetes are associated with PAD, although the overall risk profile depends on duration, glycaemic control and the presence of other cardiovascular risk factors.
High blood pressure contributes by exposing arterial walls to increased mechanical stress and promoting vascular remodelling and atherosclerosis. High concentrations of atherogenic cholesterol, particularly low-density lipoprotein cholesterol, also contribute to plaque formation. These risk factors frequently occur together, producing cumulative rather than isolated vascular effects.
Increasing age is an important non-modifiable risk factor because atherosclerotic changes accumulate over time and arterial structure and function change with ageing. A family history of PAD or cardiovascular disease can also increase susceptibility through a combination of inherited biological factors and shared environmental or behavioural factors. Chronic kidney disease is associated with increased vascular risk, partly through disturbances in mineral metabolism, inflammation and accelerated atherosclerosis.
Established coronary or cerebrovascular disease also indicates a higher likelihood of PAD because atherosclerosis is a systemic process. Ethnic and population differences in cardiovascular risk have been documented, although these reflect complex interactions among genetics, socioeconomic circumstances, prevalence of risk factors and access to healthcare rather than a single biological mechanism.
Physical inactivity and excess body weight can contribute indirectly to PAD risk through their associations with hypertension, abnormal lipids, insulin resistance, diabetes and broader cardiovascular disease. Physical inactivity does not mean that lack of exercise directly blocks an artery; rather, it can worsen the overall cardiovascular risk environment. Conversely, regular physical activity improves cardiovascular fitness and is an important part of PAD treatment. Diet can influence risk through its effects on blood lipids, blood pressure, body weight and metabolic health. Alcohol intake can also affect cardiovascular risk depending on the amount consumed. These factors interact, so an individual may develop PAD despite having relatively few conventional risk factors, while another person may have several simultaneous contributors.
PAD is usually chronic and progressive rather than the result of a single sudden blockage. However, atherosclerotic plaque can become unstable, rupture or develop a surface injury that promotes formation of a thrombus. A blood clot forming on a diseased artery can suddenly reduce or stop blood flow and cause acute limb ischaemia, which is different from the usual gradual development of stable PAD. Emboli originating elsewhere in the circulation can also obstruct a peripheral artery.
Inflammatory diseases of blood vessels, trauma, certain anatomical abnormalities and other less common vascular disorders can produce arterial narrowing or obstruction that resembles PAD but have different underlying mechanisms. Thus, while atherosclerosis accounts for most conventional PAD, not every case of reduced limb arterial flow has exactly the same cause.
The consequences of PAD are determined not only by the percentage of arterial narrowing but also by where the narrowing occurs, how quickly it developed, the extent of collateral circulation and the metabolic demands of the affected tissues. During walking, leg muscles require substantially more oxygen and blood flow, so a moderately narrowed artery may provide adequate circulation at rest but become insufficient during exercise. This produces the characteristic mechanism behind intermittent claudication.
If arterial obstruction becomes extremely severe, blood flow may become inadequate even at rest, potentially producing chronic limb-threatening ischaemia. A sudden arterial occlusion is particularly dangerous because collateral vessels do not have time to compensate. The underlying cause is therefore best understood as a disturbance of arterial structure and blood flow rather than simply the presence of cholesterol in the blood.
PAD is closely related to other manifestations of cardiovascular disease because the same atherosclerotic processes can affect arteries supplying the heart, brain, kidneys and other organs. Someone with PAD consequently has evidence of systemic vascular disease rather than merely a local circulation problem in the legs. This explains why management addresses smoking, blood pressure, cholesterol, diabetes, physical activity and overall cardiovascular risk in addition to treating leg symptoms.
Severe disease may require revascularisation by angioplasty or bypass surgery, but the need for such treatment depends on symptoms, severity and tissue viability. Importantly, risk factors are not deterministic: having a risk factor does not guarantee that PAD will develop, and some people develop PAD without an obvious single cause.
