Atherosclerosis

Etiology and Risk Factors

Elevated low-density lipoprotein (LDL) cholesterol is the major risk factor for atherosclerosis (Norris, 2020). Risk factors include (Marrs & Kosto, 2026; Mitrovic, 2019; Norris, 2020):

• Elevated LDL cholesterol and other dyslipidemias
• Increasing age
• Male sex, with risk in women rising after menopause
• Family history of premature atherosclerotic disease
• Cigarette smoking
• Hypertension
• Diabetes and insulin resistance
• Obesity, particularly visceral and perivascular fat
• Physical inactivity
• Chronic kidney disease, nephrotic syndrome, and hypothyroidism
• Elevated C-reactive protein, homocysteine, and lipoprotein(a)

Hypertension or diabetes alone roughly doubles risk, the two together increase it about eightfold, and hypertension, diabetes, and hyperlipidemia together increase it about twentyfold (Norris, 2020). Men who smoke a pack of cigarettes a day have a 70% higher death rate from ischemic heart disease than nonsmokers (Mitrovic, 2019).

Epidemiology and Clinical Context

In the United States and most developed countries, atherosclerosis has been estimated to be the underlying cause of about half of all deaths (Mitrovic, 2019). Coronary heart disease remains the leading cause of death in U.S. adults and a major cause of premature, permanent disability (Marrs & Kosto, 2026).

Atherosclerosis begins in childhood. Fatty streaks appear in the aorta in the first decade of life, in the coronary arteries in the second, and in the cerebral arteries in the third and fourth, and clinical manifestations typically do not appear for 20 years or longer (Mitrovic, 2019; Norris, 2020).

Pathophysiology

The process begins where the endothelium is under the greatest mechanical stress. Shear stress is highest at arterial branch points, where lipid accumulates most (Mitrovic, 2019).

• LDL entry and modification: LDL particles enter the subendothelial space and are oxidized or otherwise modified. Small, dense LDL particles are more atherogenic because they are oxidized more readily and penetrate the vessel wall more easily (Mitrovic, 2019).
• Inflammatory cell recruitment: Modified LDL activates innate immunity. Endothelial cells express adhesion molecules, monocytes migrate into the intima and become macrophages, and macrophages take up oxidized LDL through scavenger receptors to become foam cells, which form the fatty streak (Mitrovic, 2019; Norris, 2020).
• Endothelial dysfunction: Oxidized LDL inhibits nitric oxide production. Acetylcholine dilates a normal coronary artery but constricts an atherosclerotic one (Mitrovic, 2019).
• Smooth muscle proliferation: Cytokines and growth factors stimulate smooth muscle cells to migrate into the intima, proliferate, and produce collagen and matrix (Mitrovic, 2019).
• Plaque formation: A fibrous cap of smooth muscle cells and matrix forms over a core of lipid, foam cells, and necrotic debris. Macrophage death and cholesterol crystals sustain inflammation and necrosis (Mitrovic, 2019; Norris, 2020).

Stable plaques have a thick fibrous cap and smaller lipid core and tend to cause gradual narrowing. Vulnerable plaques have a thin, inflamed cap and a large lipid core and tend to rupture at the plaque shoulder, where the cap is thinnest and mechanical stress is highest (Norris, 2020). Rupture or ulceration with superimposed thrombosis, rather than fixed narrowing alone, usually triggers acute events (Mitrovic, 2019).

Plaques cause disease through gradual narrowing and ischemia, sudden occlusion from rupture or hemorrhage into the plaque, thrombosis and embolization, and weakening of the vessel wall that leads to aneurysm (Norris, 2020). Because flow varies with the fourth power of the vessel radius, small reductions in lumen size produce disproportionately large reductions in flow as disease advances (Norris, 2020).

Clinical Manifestations

Atherosclerosis is usually asymptomatic until a complication develops. The arteries supplying the heart, brain, kidneys, lower extremities, and small intestine are most often involved (Mitrovic, 2019; Norris, 2020).

• Coronary arteries: Narrowing of more than 75% of the lumen produces exertional angina relieved by rest. Plaque rupture and thrombosis cause myocardial infarction (Mitrovic, 2019).
• Cerebral arteries: Transient ischemic attack and thrombotic stroke (Mitrovic, 2019).
• Aorta: Aneurysmal dilation and rupture, most often in the abdominal aorta (Mitrovic, 2019).
• Renal arteries: Renovascular hypertension (Mitrovic, 2019).
• Lower extremities: Intermittent claudication, usually a cramp or ache in the calf that develops after a predictable walking distance and resolves with rest. Advanced disease produces cool feet, weak or absent pulses, pallor with elevation and dependent rubor, thin skin, rest pain, ulceration, and gangrene. Aortoiliac disease can cause buttock or hip claudication and, in men, erectile dysfunction (Norris, 2020; Seller & Symons, 2018).
• Mesenteric arteries: Intestinal ischemia, less commonly (Mitrovic, 2019).

Diagnostic Evaluation

Risk Assessment

A fasting lipid panel identifies LDL cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, and high-sensitivity C-reactive protein can serve as a marker of cardiovascular risk in apparently healthy people (Norris, 2020).

The 2026 American College of Cardiology/American Heart Association (ACC/AHA) multisociety dyslipidemia guideline recommends the AHA PREVENT equations for atherosclerotic cardiovascular disease (ASCVD) in place of the pooled cohort equations for estimating risk in primary prevention and provides LDL cholesterol goals tied to that risk. It recommends measuring lipoprotein(a) at least once in all adults, and apolipoprotein B and coronary artery calcium scoring can refine risk (Blumenthal et al., 2026; Marrs & Kosto, 2026). The course pathophysiology texts predate this guideline.

Peripheral Artery Disease

Evaluation includes inspection for chronic ischemic changes such as subcutaneous atrophy, hair loss, brittle nails, pallor, coolness, and dependent rubor; palpation or Doppler assessment of femoral, popliteal, posterior tibial, and dorsalis pedis pulses; and segmental leg pressures (Norris, 2020). An ankle-brachial index below 0.9 is abnormal, and a value below 0.4 suggests severe disease (Seller & Symons, 2018). Both legs should be examined because symptoms in one leg may limit walking enough to mask symptoms in the other (Seller & Symons, 2018).

Imaging

Ultrasound, computed tomography angiography, magnetic resonance angiography, and invasive contrast angiography can define the location and severity of arterial disease (Norris, 2020). Calcified plaques are occasionally seen on plain radiographs (Mitrovic, 2019).

Expected Findings

Findings that support clinically significant atherosclerosis include (Mitrovic, 2019; Norris, 2020; Seller & Symons, 2018):

• Elevated LDL cholesterol or other dyslipidemia
• Multiple cardiovascular risk factors
• Exertional angina or claudication relieved by rest
• Diminished or absent peripheral pulses
• Arterial bruits
• Ankle-brachial index below 0.9
• Arterial narrowing or plaque on imaging

Differential Diagnosis

Spinal Stenosis

Spinal stenosis causes exercise-related leg pain, sometimes called pseudoclaudication. Normal pedal pulses are the first clue, and the pain typically takes 10 to 30 minutes to subside and may require sitting or flexing the spine, whereas vascular claudication resolves within a few minutes of rest (Seller & Symons, 2018).

Venous Claudication

Exercise-induced calf pain in younger adults with a history of phlebitis suggests venous claudication. It is difficult to distinguish from arterial claudication, but physical signs of arterial insufficiency are usually absent (Seller & Symons, 2018).

Hip Osteoarthritis

Gluteal claudication from iliac disease is commonly mistaken for hip osteoarthritis, especially when buttock pain occurs without calf pain (Seller & Symons, 2018).

Nonatherosclerotic Arterial Disease

Vasculitis, thromboangiitis obliterans, and Raynaud phenomenon can also reduce arterial flow and must be distinguished from atherosclerosis by age, risk factors, distribution, and associated findings (Norris, 2020).

Findings That Reduce Diagnostic Probability

Few findings exclude atherosclerosis by themselves. The following findings should lower its position in the differential or prompt evaluation for an alternative:

• Normal pedal pulses with exertional leg pain that is slow to resolve with rest favor spinal stenosis over peripheral artery disease (Seller & Symons, 2018).
• A young patient with few risk factors and digital ischemia should prompt evaluation for thromboangiitis obliterans, vasculitis, or another nonatherosclerotic cause (Norris, 2020).

Treatment and Management

Lifestyle and Risk Factor Modification

Risk factor modification includes (Marrs & Kosto, 2026; Mitrovic, 2019):

• Diet limited in saturated and trans fat
• At least 150 minutes per week of moderate-intensity physical activity
• Weight management
• Smoking cessation, which reduces the risk of myocardial infarction and death
• Blood pressure control
• Diabetes management

Lowering plasma cholesterol slows the progression of atherosclerosis and in some cases reverses it (Mitrovic, 2019). In people with diabetes, rigorous blood pressure control reduces cardiovascular complications more than rigorous glucose control (Mitrovic, 2019).

Lipid-Lowering Therapy

Key principles of lipid-lowering therapy include (Blumenthal et al., 2026; Marrs & Kosto, 2026):

• Statins inhibit hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are first-line drug therapy.
• High-intensity statins, such as atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg, lower LDL cholesterol by about 50% or more. Moderate-intensity statins lower it by 30% to 49%.
• Patients with established atherosclerotic cardiovascular disease or LDL cholesterol of 190 mg/dL or higher are candidates for high-intensity therapy without further risk estimation.
• The 2026 guideline recommends lipid-lowering therapy for adults 40 to 75 years of age with at least stage 3 chronic kidney disease, type 2 diabetes, or HIV (Blumenthal et al., 2026).
• A follow-up lipid panel 4 to 12 weeks after starting therapy assesses response and adherence.
• Ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody may be added to maximally tolerated statin therapy when additional LDL lowering is needed.

Peripheral Artery Disease

Antiplatelet agents reduce thrombotic risk, and statins lower cholesterol. Walking to the point of claudication may encourage collateral circulation. Percutaneous or surgical revascularization is typically reserved for disabling claudication or limb-threatening ischemia, and patients should be evaluated for coexisting coronary and cerebrovascular disease (Norris, 2020).

Interventions Without Proven Benefit

Antioxidant supplements such as vitamin E and β-carotene have been disappointing in human trials. B vitamins lower homocysteine, but evidence that this reduces atherosclerotic events is inconclusive (Mitrovic, 2019).

Complications and Red Flags

Urgent escalation is required for:

• Acute coronary syndrome symptoms, a new focal neurologic deficit, or acute limb ischemia
• Sudden abdominal, back, or flank pain concerning for aortic aneurysm or rupture, or abdominal pain out of proportion to examination suggesting mesenteric ischemia
• Rest pain, nonhealing ulceration, or gangrene indicating limb-threatening ischemia

Complications include myocardial infarction, stroke, aneurysm rupture, renovascular hypertension, limb loss, and intestinal ischemia (Mitrovic, 2019; Norris, 2020).

Clinical Reasoning Priorities

Most acute events begin when a plaque ruptures and a thrombus forms on its surface, so a patient with minimal symptoms can still be at substantial risk (Mitrovic, 2019). Risk assessment and risk factor treatment are central to management long before symptoms appear (Marrs & Kosto, 2026).

When atherosclerosis is found in one arterial bed, look for it in others. Peripheral artery disease, carotid disease, and coronary disease share the same risk factors and frequently coexist (Norris, 2020).

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References

Blumenthal, R. S., Morris, P. B., Gaudino, M., Johnson, H. M., Anderson, T. S., Bittner, V. A., Blankstein, R., Brewer, L. C., Cho, L., de Ferranti, S. D., Gianos, E., Gluckman, T. J., Gradney, K. F., Isiadinso, I., Lloyd-Jones, D. M., Marrs, J. C., Martin, S. S., McLain, K. H., Mehta, L. S., . . . Wilkins, J. T. (2026). 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 153(17), e1154–e1276. https://doi.org/10.1161/CIR.0000000000001423

Marrs, J. C., & Kosto, M. D. (2026). Dyslipidemia. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed.). McGraw Hill.

Mitrovic, I. (2019). Cardiovascular disorders: Vascular disease. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer. Seller, R. H., & Symons, A. B. (2018). Differential diagnosis of common complaints (7th ed.). Elsevier.