Authors: Ahmed Elsherif 1 ; Michelle Wyatt 2
Peer Reviewers: Stanley Oiseth 3 ; Joseph Alpert 4
Affiliations: 1 Suez Canal University; 2 Medical Editor at Lecturio; 3 Chief Medical Editor at Lecturio; 4 Tucson University, Arizona

Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel wall. For the most part, it is an irreversible process, and clearly defined risk factors can be reduced through changes in lifestyle including diet, exercise, maintaining a healthy weight, and smoking cessation. [5,24] Medications may cause plaque regression in some cases. [19] Atherosclerosis manifests as arterial stenosis and is also a source of thromboembolic disease. The clinical presentation depends on the specific vessels affected, including coronary artery disease, carotid disease, cerebrovascular disease, and peripheral vascular disease.[1] As the most common primary disease of the arterial vascular system, atherosclerosis is a leading cause of death worldwide due to myocardial infarction, stroke, aortic aneurysms and dissection, and renal failure due to renovascular disease.[2]

For further review of this topic, including links to video lectures by specialists in the field, follow this link:

This article is not intended to substitute for professional medical advice and should not be relied on as health or personal advice. Always seek the guidance of your doctor or other qualified health professional with any questions you may have regarding your health or a medical condition.


Atherosclerosis is the thickening of the arterial wall and loss of elasticity due to variable pathogenesis. The term atherosclerosis is derived from the Greek words “athērē” meaning a substance like hulled grain kernels or porridge, plus “sklērōsis” meaning hardening. The changes in atherosclerosis occur in the intima and media of blood vessel walls and lead to stiffening the vessel walls and narrowing the vascular lumen.[1]


Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Within the USA and EU, atherosclerosis involving the coronary, cerebral, and peripheral arteries accounts for more morbidity and mortality than any other disease (approximately 50% of all deaths), with many deaths occurring under age 65.[2,3]


Atherosclerosis is a chronic inflammatory disorder that occurs in the walls of blood vessels. Oxidized low-density lipoprotein (LDL) cholesterol is involved in the inflammatory process.[4] Lipids, calcium, and other cellular debris are stored in the intima of large and medium-sized arteries, thereby causing the inflammatory process to cause vessel wall thickening and plaque formation.

Hyperlipidemia, especially hypercholesterolemia, is a significant risk factor for atherosclerosis. LDL cholesterol (“bad cholesterol”) is the primary culprit in the clogging of arteries. The lipid-cholesterol-protein complex delivers cholesterol to peripheral tissues; at the same time, high-density lipoprotein (HDL) mobilizes cholesterol from the periphery (even from atheromas) and transports it to the liver for catabolism and biliary excretion. High HDL (“good cholesterol”) levels are associated with reduced risk of atherosclerosis; low levels correlate with higher risk. Hypercholesterolemia can be caused by abetalipoproteinemia, lipoprotein lipase, apolipoprotein C-II deficiencies, and familial dysbetalipoproteinemia.[5]

Risk Factors


Drawing of a cross-section of an artery, comparing a normal intimal layer (endothelium) and medial layer (smooth muscle). Note how the damaged endothelium on the right leads to inflammatory changes with lipid and calcium deposition resulting in vessel narrowing by an atherosclerotic plaque. Image:Coronary atherosclerosis.” by Subbotin, V.M. License: CC BY 2.0

The risk factors associated with the development of atherosclerosis are divided into modifiable and nonmodifiable risk factors. Nonmodifiable risk factors are male sex, age, genetic abnormalities, and family history. The modifiable risk factors include hypertension, hyperlipidemia, cigarette smoking, and diabetes.[6] The modifiable factors can be subdivided into first and second-order risk factors.

First-Order Modifiable Risk Factors

  • Cigarette smoking promotes early development and rapid progression of atherosclerosis.
  • Arterial hypertension: Due to the high-pressure load, endothelial damage occurs faster.
  • Diabetes mellitus: Increased blood glucose levels cause reactive glycosylation, causing increased phagocytosis and endothelial damage.
  • Hyperlipidemia: Excessive LDL cholesterol increases the risk of atherosclerosis, especially if HDL cholesterol levels are also low.

Second-Order Modifiable Risk Factors

  • Lack of exercise 
  • Psychological or emotional stress 
  • Obesity 
  • Hyperuricemia 
  • Hypertriglyceridemia 
  • Hyperglycemia and diabetes mellitus
  • Increased lipoprotein (a)


There are four types of arteriosclerosis, the general term for “hardening of the arteries.” Macroangiopathy refers to changes in large and medium-sized arteries. In contrast, in patients with hypertension, microangiopathy refers to the pathologic changes in the arterioles, also called arteriolosclerosis. 

The four types of arteriosclerosis are atherosclerosis (the most common), arteriolosclerosis, Mönckeberg medial sclerosis (characterized by calcifications of the medial walls of muscular arteries), and fibromuscular intimal hyperplasia (in muscular arteries larger than arterioles, caused by inflammation or injury)

Hyaline arteriolosclerosis, in response to hypertension, shows homogeneous, pink hyaline thickening of the arterioles due to plasma protein leakage across injured endothelial cells and increased smooth muscle cells (SMCs). This results in luminal narrowing and is more severe in patients with diabetes. Hyperplastic arteriolosclerosis occurs in severe cases of hypertension; the arterioles show concentric, laminated (“onion-skin”) thickening of the walls due to SMC proliferation and thickened, reduplicated basement membranes. In patients with severe or malignant hypertension, fibrinoid deposits and vessel wall necrosis (necrotizing arteriolitis) are seen most notably in the kidney.

The Various Degrees of Severity of Atherosclerosis

Mild Moderate Severe
  • Endothelium becomes damaged
  • Factors: hypertension, smoking
  • Damage causes an inflammatory response and WBCs deposit cholesterol, forming an atheroma
  • Calcium and fibrous tissue form a plaque
  • Artery loses elasticity and narrows
  • Plaque restricts blood flow and increases blood pressure
  • Increased blood pressure promotes the formation of more plaque

Clinical Features

Atherosclerosis can be present for years and decades without any symptoms. Common manifestations include coronary artery disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm.

High-yield fact:

Metabolic syndrome refers to the presence of at least 3 of these 5 risk factors: [7] 

  • Abdominal obesity (waist circumference > 102 cm (40 inches) in men,  > 88 cm (35 inches) in women).
  • Triglycerides ≥ 150 mg/dL or drug treatment for elevated triglycerides
  • HDL cholesterol < 40 mg/dL in men or < 50 mg/dL in women, or drug treatment for low HDL cholesterol
  • Fasting plasma glucose > 100 mg/dL or drug treatment for elevated blood glucose 
  • Blood pressure > 130/85 mm Hg or drug treatment for hypertension

Patients with metabolic syndrome and an elevated albumin-to-creatinine ratio or elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have an elevated risk of CHD mortality. [8]


The current theory of pathogenesis is called the “response to injury” hypothesis. The endothelium is injured first, inflammation occurs, and atherosclerosis results from chronic inflammatory and healing responses of the arterial wall.[9] Early and evolving changes involve the progression of a complex interaction of modified lipoproteins, macrophages, and T lymphocytes with endothelial cells (ECs) and smooth muscle cells (SMCs) of the arterial wall. In summary, atherosclerosis progresses in the following sequence [4]: 

  • Endothelial injury and dysfunction, increased vascular permeability; leukocyte adhesion and thrombosis
  • Disruption of nitric oxide (NO) synthesis; endothelial dysfunction occurs due  to the endothelial injury
  • Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall
  • Adherence of monocytes to the endothelium; migration into the intima and transformation into macrophages and foam cells (containing lipid vacuoles)
  • Platelet adhesion
  • Factor release from activated platelets, macrophages, and endothelial cells; SMC recruitment.
  • SMC proliferation, extracellular matrix (ECM) production, and T cell recruitment
  • Lipid accumulation both extracellularly and within cells (macrophages and SMCs)
  • Calcification of ECM and necrotic debris (late in the pathogenesis)

Initially, LDL cholesterol is deposited in the intima of the vessel wall. It is then oxidized and is followed by a local inflammatory response, i.e., monocytes start migrating into the tissue. After they phagocytize the LDL cholesterol, foam cells containing lipid vacuoles are formed. These early atherosclerotic lesions are called fatty streaks and occur especially in areas with high mechanical stress (for example, at the proximal left anterior descending artery (LAD) and the carotid bifurcation).

Gradually, there is an accumulation of lipids and cellular debris in the intima. Different cells within the vessel walls release mediators, and muscle cells from the tunica media migrate into the intima and proliferate.

The fatty core is surrounded by connective tissue, making it dense and inaccessible; hence, the stored LDL cholesterol cannot be degraded. These plaques may contain newly-formed vessels (originating from the vasa vasorum) that can bleed into the plaque. Calcium starts to accumulate in the growing plaque. 


Typical disease progression of atherosclerotic and aneurysmal disease. (A) Chronological atherosclerotic plaque formation starting with endothelial dysfunction and ending in lipid core formation and turbulent, reduced blood flow; (B) Chronological aneurysm formation highlighting similar early steps, but resulting in extracellular matrix degradation, vessel expansion, and turbulent flow. Image: “Typical Disease Progression of Atherosclerotic and Aneurysmal Disease” by Lin, J.B., et al. License: CC BY 4.0

Plaques with a sizeable lipid core and only a thin fibrous cap are at risk of rupture, leading to such intense activation of the coagulation system that complete thrombotic occlusion of a vessel occurs. 

Plaque rupture can also cause cholesterol emboli to migrate to remote blood vessels, for example, the renal arteries. 

Another consequence of atherosclerosis is the formation of an aneurysm mainly caused by extracellular matrix degradation and interference with the vascular supply of the tunica media.

Critical stenosis is the degree of plaque occlusion severe enough to cause tissue ischemia, thought to be 70%–75% stenosis in coronary and most other arteries.[10] At this level, the arteries can not dilate sufficiently to supply enough blood when there is an increase in oxygen demand, and chest pain may occur with exertion, as in stable angina. More severe stenosis leads to an increased imbalance between oxygen demand and supply, leading to more severe ischemic heart disease, including ischemic cardiomyopathy and infarction.

History and Physical Examination of Atherosclerosis

A patient’s history helps identify risk factors and should include family history. The patient should also be asked about comorbidities, medications, and walking distance tolerance. 

Physical examination provides information including skin color, temperature, and ulcerations due to peripheral artery disease. Blood pressure measurement is essential. Cardiac auscultation may (or may not) give information about the presence of coronary artery atherosclerosis. An abdominal exam may reveal a systolic bruit due to renal artery stenosis or an enlarged abdominal aorta. ECG or stress testing can be helpful if significant positives are found on history and exam. [11] 

Laboratory Tests

A lipid profile includes total cholesterol, LDL, HDL, and triglycerides in identifying patients at risk of atherosclerosis. If myocardial infarction is suspected, cardiac enzymes including troponin I and CK-MB are necessary.

A lab test for inflammation, highly sensitive-C-reactive protein (hs-CRP), has been established as a biomarker for atherosclerosis and may identify patients at increased risk of cardiovascular disease.[12,13] It is elevated in patients with other atherosclerotic cardiovascular disease (ASCVD) risks such as smoking and diabetes mellitus. There is also a positive relationship between the elevated liver enzyme alanine aminotransferase (ALT) and heart disease risk.

Fasting blood glucose and hemoglobin A1c (HbA1c) are needed to diagnose diabetes mellitus or follow-up glucose control in patients with uncontrolled diabetes, a significant contributing factor to both macrovascular and microvascular disease. [14]

Other tests include:

  • Complete blood count
  • Comprehensive metabolic panel (CMP) for electrolytes and renal function
  • Thyroid function tests
  • Rheumatoid factor in patients with suspected rheumatoid arthritis

Diagnostic Imaging


Doppler sonography offers a painless, non-invasive way to view the atherosclerotic burden of blood vessels. It is used to determine the ankle-brachial index, an indicator of the severity of peripheral vascular disease in the lower extremities. There is some concern about the variability between personnel who perform the test and, thus, its reliability. [15]

Color duplex sonography combines two methods, allows the examination of vessel sections, and gives a color code depending on the blood flow. Intravascular ultrasound (IVUS) can be used to assess coronary arteries and provide guidance for placing drug-eluting stents.[16]

An echocardiogram is done to assess structural or functional abnormalities of the heart. It is used to estimate the ejection fraction and observe the contractility of the heart for wall motion abnormalities, two important functional parameters.[17]


CT and MR angiography also offer the advantage of non-invasive diagnostics over conventional angiography because of the better detail provided, with 3-D reconstruction possible for precise treatment planning. CT angiography provides a rapid assessment, especially in emergency diagnosis, whereas MR angiography has the advantage of low radiation exposure. Conventional angiography has the advantage of being able to perform simultaneous interventions such as stent angioplasty.


Example of a runoff CT angiography (CTA) with sufficient diagnostic confidence and diagnostic image quality. 69-year-old woman with intermittent claudication of the left lower leg due to atherosclerosis in the peripheral arteries. Run-off CTA shows multiple stenoses (white arrows) of the left superficial femoral artery in the maximum intensity projection images (a) and curved multiplanar reformat (b). Stenoses were confirmed by digital subtraction angiography (DSA) (c) and successfully treated by percutaneous transluminal angioplasty and stenting (d, open white arrows show restoration of blood flow in the previously narrowed artery). Image: by Werncke, T., et al. License: CC BY 4.0

Differential Diagnoses

Vascular Diseases Similar to Atherosclerosis

In addition to atherosclerosis, other vascular diseases cause structural wall changes and lead to arterial stenosis. Inflammation caused by autoimmune or infectious conditions causes 5% of stenotic vascular disease. The vascular wall thickens with inflammatory infiltrates and secondary vessel wall edema, resulting in vasculitis. Damage to the endothelium results in thrombosis. In addition to stenosis, the inflammatory process can lead to vascular wall dilation or dissection.

Other causes of arterial damage

Vasculitis is caused by inflammatory WBCs in blood vessel walls with reactive damage. Loss of endothelial integrity can compromise the lumen resulting in tissue ischemia and necrosis similar to that seen with atherosclerosis. Autoimmune causes of vasculitis include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and anti-glomerular basement membrane autoantibody disease. [18]

Buerger disease (thromboangiitis obliterans) is a nonatherosclerotic inflammatory disorder that can cause occlusive thrombus but spares the blood vessel wall.

Giant cell arteritis involves large- and medium-sized arteries, specifically the cranial branches of the carotid artery such as the temporal artery, with inflammatory infiltrates causing loss of vascular smooth muscle cells and elastic fibers that may cause an aneurysm.

Takayasu arteritis affects large blood vessels by lymphocytic infiltrates in the aorta causing vascular injury by releasing the cytolytic protein perforin. This inflammation can lead to narrowing, occlusion, or dilation of the involved areas of the arteries.

Bacteria such as E. coli, S. aureus, and viruses such as herpesviruses can also cause vessel wall inflammation. 

Mechanical Damage

Mechanical damage, such as trauma to arterial vessels, can cause stenosis by secondary inflammatory changes. Malignant tumors can cause infiltrative growth in the vascular wall. Even benign tumors can result in vasoconstriction by external compression.


These include weight normalization combined with aerobic physical activity such as jogging, swimming, or cycling and eating a healthy diet. Smoking cessation is also important, and stress reduction with active relaxation techniques such as meditation are beneficial for cardiovascular risk reduction.[20]

Non-pharmacological Treatment (lifestyle modifications)

These include weight normalization in combination with sufficient aerobic physical activity such as jogging, swimming, or cycling and eating a healthy diet. Smoking cessation is also important, as well as avoiding stress.

Walking Exercise Strategy

Exercising, such as walking regularly at least 30 continuous minutes 3 times per week, can improve symptoms by encouraging the formation of new collateral blood vessels and improving muscle efficiency. Many patients experience a dramatic increase in the distance they can walk without pain. Patients also benefit from a vascular rehabilitation program involving 45 minutes of supervised exercise weekly.[21]

Pharmacological Treatment

Pharmacological treatment aims to control the modifiable risk factors of atherosclerosis. Antihypertensives, lipid-lowering agents, and anticoagulant medications treat atherosclerosis and its complications.


Complications include ischemic heart disease (IHD), angina pectoris, cerebrovascular disease, stroke, peripheral artery disease (PAD), and renal artery stenosis. Subclavian steal syndrome and mesenteric stenosis can also result from chronic arterial stenosis.

Acute vascular occlusions can also cause complications. Mesenteric infarction, renal or splenic infarction, transient ischemic attack (TIA), and stroke are seen due to thrombi or emboli occluding an already atherosclerotic artery. Aneurysms at various vessel segments, such as infrarenal or thoracic aortic aneurysms (and possible thoracic aortic dissection), as well as iliac or popliteal aneurysms, are potential consequences of atherosclerosis.


Modifiable risk factor reduction is essential. Prevention aims primarily to promote a healthy diet, get adequate physical activity with aerobic exercise, and control underlying diseases like diabetes mellitus and hypertension. Smoking cessation is the most important measure in preventing atherosclerosis and its complications.



Dyslipidemia is a disorder of lipid metabolism that is clinically defined as the presence of one of the following abnormalities: elevated plasma triglycerides (TG), elevated total cholesterol (TC), high levels of low-density lipoprotein (LDL), and decreased high-density lipoprotein (HDL). The specific population values will differ according to age, gender, and race. It is one of the leading causes of the development of atherosclerosis.


Causes of dyslipidemia can be primary as in familial hypercholesterolemia or secondary to underlying diseases such as diabetes mellitus, hypothyroidism, nephrotic syndrome, and hepatic disorders.

Clinical Features

Dyslipidemia is usually asymptomatic and is seen in >70% of patients with premature coronary heart disease. Yellowish plaques with lipid-laden histiocytes surrounding blood vessels are sometimes found on the skin around patients’ eyes (xanthelasmas) or over the joints or tendons (xanthomas). Other clinical features of dyslipidemia include corneal arcus (“arcus senilis”) and hepatosplenomegaly. Dyslipidemia is often diagnosed on routine investigations or after a cardiovascular event such as a myocardial infarction or stroke.

An important cause of dyslipidemia is familial hypercholesterolemia (FH), one of the most common serious hereditary disorders, with heterozygotes occurring in 1/250 people. It should be suspected in individuals with fasting LDL cholesterol levels above 190 mg/dL or non-HDL cholesterol above 220 mg/dL or in family members of patients with total cholesterol above 240 mg/dL. FH has an autosomal dominant pattern of inheritance and is caused by mutations in the genes encoding the LDL receptor (85% cases), ApoB protein (5%–10% cases), or activating mutations of PCSK9 (1%–2% cases). Hypercholesterolemia develops as a consequence of impaired transport of LDL into the cells. Homozygotes have a greater increase in serum cholesterol and a higher frequency of ischemic heart disease.[22]

Frederickson Classification of Lipid Disorders  [23]

Type Typical Lipid Levels Lipoprotein Abnormality
I TG > 99th percentile Chylomicrons
IIa TC > 90th percentile; apoB ≥ 90th percentile (depends on type) LDL
IIb Depending on type, TC and/or TG ≥ 90th percentile and apo B ≥ 90th percentile LDL and VLDL
III TC and TG > 90th percentile Remnants of VLDL (Intermediate density lipoprotein) and chylomicrons
IV TC > 90th percentile; depending on type, +/- TG > 90th percentile, or low HDL VLDL
V TG > 99th percentile VLDL and chylomicrons

TG: triglycerides; TC: total cholesterol; LDL: low-density lipoprotein; VLDL: very-low-density lipoprotein; HDL: high-density lipoprotein.


Non-Pharmacological Treatment (Lifestyle Modification)

Lifestyle modifications remain an essential therapeutic option for controlling dyslipidemia. These modifications include:

  • Dietary changes: reduce saturated fat intake
  • Weight reduction if overweight
  • Daily aerobic exercise or regular exercise

High-yield fact:

Regular exercise is proven to increase HDL and decrease LDL levels.[24]

Pharmacological Treatment

Statin therapy

The American Heart Association recommends a moderate-intensity statin for primary prevention of ASCVD in adults ages 40–75 without diabetes mellitus who have a 10–year atherosclerotic cardiovascular disease risk of 7.5–20%.[25]

High-intensity statin therapy is recommended for high-risk patients with a10–year ASCVD risk > 20%) or those who already have ASCVD.

Note 1:

  • The goal is to achieve a 50% reduction of the baseline LDL value. 

Note 2:

  • High-intensity statins include rosuvastatin 20 or 40 mg and atorvastatin 40 or 80 mg.
  • Moderate-intensity statins include rosuvastatin 5 or 10 mg and atorvastatin 10 or 20 mg.

Contraindications to Statins

Statins are contraindicated in patients with active liver disease and pregnancy. Although the incidence of recorded adverse effects is low, the side effect of musculoskeletal pain is seen clinically in 22% of patients on statins (compared to 17% of those not on statins). The main side effects of statins are:

  • Myopathies (1%)
  • Rhabdomyolysis (0.2%) 
  • Elevated liver function tests (2%) 

Other side effects of statins include confusion, forgetfulness, dementia, depression, and erectile dysfunction. 

The introduction of statins to manage hyperlipidemia has improved the prognosis of IHD.

Statins are also effective in lowering the risk of recurrent stroke in patients with a previous history of cerebrovascular disease. However, a definite mortality benefit has been more challenging to demonstrate consistently with statin treatment. Intense LDL-C lowering lowers the risk of all-cause death in those at very high risk [26]. Initiating statins to lower LDL cholesterol levels in the acute setting of a cerebrovascular accident was proven to improve clinical outcomes and reduce the disability of such patients.

Non-statin therapy

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are now being used to decrease LDL cholesterol levels associated with cardiovascular disease. PSCK9 is an enzyme produced in the liver that binds to the LDL receptors on hepatocytes, resulting in higher plasma LDL cholesterol levels. Blocking this enzyme with monoclonal antibodies (e.g., alirocuman, evolocumab) is associated with lower rates of myocardial infarction and stroke.[29, 30]

Ezetimibe inhibits cholesterol absorption at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1), and is offered to patients who cannot tolerate statins. PCSK9 monoclonal antibodies (alirocumab and evolocumab) bind free plasma PCSK9, an enzyme that degrades the receptor for LDL (LDL (LDL-R), leading to higher hepatic LDL-R expression and lower plasma LDL-C levels. This treatment is recommended for those whose LDL-C remains above 70 mg/dL. [27,28]. Other lipid-lowering medications that can be used to lower the LDL cholesterol level include icosapent ethyl (an omega-3 fatty acid) and fibrates (more often used for hypertriglyceridemia). Bile acid sequestrants (e.g., cholestyramine, colestipol, and colesevelam) and nicotinic acid (niacin) are rarely used because of their side effects; however, nicotinic acid is used to lower lipoprotein(a). 

Review Questions

  1. Which vascular area is prone to be affected by atherosclerosis?
    1. Arteries in the extremities
    2. All coronary arteries
    3. Intracranial arteries
    4. Carotid artery bifurcation
    5. Renal arteries
  2. What best describes the composition of an atherosclerotic plaque?
    1. Cholesterol
    2. Lipids and cellular debris
    3. Smooth muscle
    4. Fibrin
    5. Collagen
  3. Which of these conditions is not related to atherosclerosis?
    1. Peripheral artery disease
    2. Coronary heart disease
    3. Prinzmetal angina
    4. Stroke
    5. Mesenteric artery stenosis

Answers: 1D, 2B, 3C

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