Peripheral artery disease (PAD) is caused by atherosclerosis, a gradual buildup of fatty deposits inside the arteries that supply blood to your legs and feet. An estimated 113 million people over age 40 have the condition worldwide, and while it shares the same underlying process as heart disease, certain risk factors hit peripheral arteries especially hard.
How Plaque Builds in Your Arteries
PAD starts with damage to the inner lining of an artery. This lining, called the endothelium, normally keeps blood flowing smoothly and prevents substances from seeping into the artery wall. When that lining is injured by high blood pressure, high blood sugar, or chemicals from cigarette smoke, it stops working properly. The artery wall becomes “leaky,” allowing cholesterol and other fats to slip underneath.
Once trapped beneath the artery lining, those fats undergo chemical changes. They become oxidized, which triggers the immune system to respond as if fighting an infection. White blood cells rush in and try to absorb the oxidized fat, swelling into what scientists call foam cells. These foam cells accumulate, forming the core of a plaque. Over time, the artery wall remodels around the plaque: smooth muscle cells migrate inward, a fibrous cap forms over the fatty core, and the channel available for blood flow gradually narrows.
The process feeds on itself. Dead cells inside the plaque release inflammatory signals that attract more immune activity. Normally, the body has a cleanup system that removes dead cells, but inside a growing plaque this system breaks down. The result is a necrotic core that makes the plaque unstable and prone to rupture, which can trigger a blood clot that blocks the artery entirely.
Smoking Is the Strongest Risk Factor
No single risk factor drives PAD more powerfully than smoking. A large study from Johns Hopkins found that people who smoked more than a pack a day had 5.4 times the risk of developing PAD compared to people who never smoked. Even at lower levels of exposure, smoking more than 40 pack-years (roughly a pack a day for 40 years, or two packs a day for 20 years) quadrupled the risk.
What makes smoking’s relationship with PAD distinctive is how long the damage lingers after quitting. For heart disease and stroke, former smokers see risk reductions of 30 to 40 percent within five to nine years. For PAD, the drop is steeper at 57 percent in that same window, but full recovery takes much longer. Former smokers’ PAD risk doesn’t return to the baseline level of a never-smoker until about 30 years after quitting. That timeline suggests smoking inflicts lasting structural changes on peripheral arteries that take decades to repair.
How Diabetes Damages Peripheral Arteries
Chronically elevated blood sugar injures artery walls through several overlapping mechanisms. High glucose levels generate harmful molecules called advanced glycation end products, which essentially act like chemical cross-links, stiffening artery walls and promoting inflammation. At the same time, excess sugar throws off the balance of nitric oxide, a molecule your arteries depend on to stay relaxed and dilated. With less nitric oxide available, arteries constrict and become less responsive to normal blood flow signals.
Diabetes also impairs the body’s ability to grow new blood vessels around a blockage, a natural workaround called collateral circulation. In people without diabetes, when an artery narrows, nearby smaller vessels can enlarge to reroute some blood flow. Persistent high blood sugar disrupts signaling pathways that control this process, particularly by degrading a key receptor that blood vessel growth depends on. The result is that people with diabetes tend to develop more severe PAD, with worse blood flow to the feet and higher rates of tissue loss and amputation.
High Cholesterol and High Blood Pressure
Cholesterol is the raw material of plaque. When LDL cholesterol circulates at high levels, more of it penetrates damaged artery walls and accumulates. This isn’t a passive deposit like sediment in a pipe. The trapped cholesterol actively drives inflammation, recruits immune cells, and promotes clot formation on the plaque surface. Reducing LDL levels slows this cycle at its source.
High blood pressure contributes differently. The mechanical force of elevated pressure batters the artery lining with every heartbeat, accelerating the endothelial damage that lets the whole process begin. Peripheral arteries in the legs are already subject to significant pressure changes during walking and standing, so chronically elevated blood pressure compounds the stress on vessels that are already working hard.
Chronic Inflammation as a Driver
Atherosclerosis is fundamentally an inflammatory disease, and some people carry a higher baseline level of inflammation even without obvious risk factors. C-reactive protein (CRP), a marker of systemic inflammation measured through a simple blood test, predicts PAD risk independently of cholesterol or blood pressure. In a study of apparently healthy men, those with the highest CRP levels had 2.1 times the risk of developing symptomatic PAD compared to those with the lowest levels.
This helps explain why PAD sometimes develops in people who seem otherwise healthy. Conditions that promote chronic low-grade inflammation, including autoimmune diseases, obesity, chronic kidney disease, and even gum disease, may contribute to arterial damage in ways that standard cholesterol tests don’t capture.
Who Gets PAD Most Often
PAD becomes dramatically more common with age. Global prevalence sits around 1.5 percent for everyone over 40, but that number climbs to nearly 15 percent in people aged 80 to 84. Women are affected slightly more often than men overall, though men tend to develop symptoms at younger ages.
Family history plays a role as well. Genome-wide studies have identified 19 genetic variants consistently associated with PAD, including variants linked to how the body handles inflammation, processes fats, and maintains blood vessel walls. Having a parent or sibling with PAD or other cardiovascular disease raises your risk, particularly if they developed it before age 60.
Less Common Causes Beyond Plaque
While atherosclerosis accounts for the vast majority of PAD cases, a few other conditions can restrict blood flow in the legs, particularly in younger patients who don’t have typical risk factors.
- Buerger’s disease is an inflammatory condition that affects small and medium arteries, almost exclusively in people under 50 who smoke heavily. Rather than gradual plaque buildup, the artery walls themselves become inflamed and clot off in segments. Symptoms often start in the fingers or toes with ulcers, color changes, or intense pain.
- Popliteal artery entrapment occurs when a calf muscle or ligament physically compresses the main artery behind the knee. It typically affects younger, athletic individuals and causes calf pain or cold feet during exercise that resolves with rest. A hypertrophied calf muscle can also create a functional version of this problem.
- Cystic adventitial disease is rare and mostly found in middle-aged men. A cyst filled with gel-like material forms in the outer wall of the artery (usually behind the knee) and squeezes the channel shut. One telltale feature: pain lingers for up to 20 minutes after stopping activity, much longer than the quick relief typical of standard PAD.
How PAD Is Detected
The primary screening tool for PAD is the ankle-brachial index, a painless test that compares blood pressure readings at your ankle and your arm. A normal ratio is above 1.0, meaning pressure at the ankle is equal to or slightly higher than at the arm. A reading of 0.91 to 1.00 is considered borderline. A ratio of 0.90 or below indicates PAD, with lower numbers reflecting more severe blockages and reduced blood flow to the feet.
Many people with PAD have no symptoms at all, or they attribute leg fatigue and cramping to aging. The classic symptom, cramping pain in the calves during walking that goes away within a few minutes of rest, occurs in only a fraction of people with measurable disease. This is why screening matters if you have multiple risk factors, even if your legs feel fine.