Atherosclerosis is characterized by lesions that begin in the intima of affected arteries, involving the sequential accumulation of intracellular and extracellular lipids, fibrous tissue proliferation, and calcium deposition. Lesions contain monocytes, macrophages, and other inflammatory cells, along with the migration and proliferation of smooth muscle cells. A large amount of connective tissue matrix, including collagen fibers, elastic fibers, and proteoglycans, is formed. The arterial media may also undergo gradual degeneration and calcification. On this basis, complications such as intraplaque hemorrhage, erosion, rupture, and secondary local thrombosis may occur. The lipid accumulation in the arterial intima appears yellow and atheromatous, giving the condition its name, atherosclerosis. Cardiovascular diseases related to atherosclerosis are collectively referred to as atherosclerotic cardiovascular disease (ASCVD).
Etiology and risk factors
The exact cause of atherosclerosis is not fully understood. Epidemiological studies have identified several factors associated with an increased incidence of the disease. These factors are not direct causes but act at various stages of disease progression. They are referred to as risk factors. The main risk factors are as follows:
- Age and gender
- Dyslipidemia
- Hypertension
- Diabetes and impaired glucose tolerance
- Smoking
- Obesity
- Family history
Age and gender
The incidence of atherosclerosis increases with age. It is more common in adults over 40 years old, with a faster progression after the age of 49. In recent years, the onset age has shown a trend of becoming younger. Males have a higher incidence than females, with the disease appearing approximately 10 years earlier in males. This may be related to the anti-atherosclerotic effects of estrogen. However, the incidence in females increases rapidly after menopause. Age and gender are considered non-modifiable risk factors.
Dyslipidemia
Lipid metabolism disorders are the most important risk factors for atherosclerosis. The condition is commonly seen in individuals with hypercholesterolemia and is related to cumulative cholesterol exposure. Individuals with familial hypercholesterolemia can develop atherosclerosis as early as adolescence. Experimental animals fed high-cholesterol diets develop atherosclerosis. Increased levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), or very-low-density lipoprotein cholesterol (VLDL-C), elevated apolipoprotein B (apo B), and decreased high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A (apo A) are all considered risk factors. Among these, the role of LDL-C in promoting atherosclerosis is the most well-established. Elevated lipoprotein(a) [Lp(a)] and TG may also be independent risk factors. In clinical practice, LDL-C is the primary target for ASCVD prevention and treatment, with non-HDL-C as a secondary target.
Hypertension
The incidence of atherosclerosis is significantly higher in patients with hypertension. This may be due to endothelial cell damage caused by hypertension, which facilitates the entry of LDL-C into the arterial wall and stimulates smooth muscle cell proliferation, leading to the development and progression of atherosclerosis. Approximately 60%-70% of patients with coronary atherosclerosis also have hypertension, and hypertensive individuals have a 3-4 times higher risk of developing coronary artery disease.
Diabetes and impaired glucose tolerance
At the time of diagnosis, approximately 50% of patients with type 2 diabetes already have atherosclerotic lesions. Type 2 diabetes is considered an equivalent risk to coronary heart disease. The incidence of atherosclerosis in diabetic patients is 2-4 times higher than in non-diabetics. The lesions occur earlier, are more diffuse, progress more rapidly, and involve more vascular beds. Diabetic patients often have dyslipidemia, characterized by elevated TG, reduced HDL-C, and increased small dense LDL (sdLDL). When combined with hypertension, the incidence of atherosclerosis increases significantly. Diabetic patients also frequently exhibit elevated coagulation factor VIII and enhanced platelet function, accelerating thrombus formation and vascular occlusion. Even during the stage of impaired glucose tolerance, the risk of atherosclerosis increases, which is closely related to insulin resistance.
Smoking
Compared with non-smokers, smokers have a 2-6 times higher incidence and mortality rate of atherosclerosis, which is directly proportional to the number of cigarettes smoked daily. Passive smoking is also a risk factor. Harmful components in tobacco can damage vascular endothelium, reduce prostacyclin release, and promote platelet adhesion and aggregation on the arterial wall, leading to thrombosis. Smoking also lowers HDL-C levels and raises TC levels. Additionally, nicotine in tobacco can directly affect coronary arteries and the myocardium, causing arterial spasm and myocardial damage.
Obesity
Body mass index (BMI) is calculated as weight (kg) divided by height squared (m2). A BMI of 24-27.9 kg/m2 is classified as overweight, while a BMI ≥28 kg/m2 is classified as obese. Obesity can lead to elevated levels of TG and cholesterol and is often accompanied by hypertension, diabetes, or insulin resistance, all of which significantly increase the incidence of atherosclerosis.
Family history
A family history of early-onset ASCVD is defined as clinical ASCVD occurring in male first-degree relatives under 55 years old or female first-degree relatives under 65 years old. Familial hypercholesterolemia, an autosomal dominant condition, is a common cause in such families. Additionally, more than 200 susceptibility or mutation genes related to atherosclerosis risk factors have been identified in recent years.
Other risk factors
Type A personality
Individuals with excessive mental stress are more prone to the disease, possibly due to chronically elevated catecholamine levels.
Oral contraceptives
Long-term use of oral contraceptives can increase blood pressure, cause dyslipidemia and impaired glucose tolerance, and alter coagulation mechanisms, increasing the risk of thrombosis.
Unhealthy lifestyle habits
High-calorie diets rich in animal fat, cholesterol, and sugar, along with a lack of physical activity, contribute to the disease.
Sleep disorders
Chronic insomnia or insufficient sleep (less than 6 hours per day) is also associated with an increased risk of atherosclerosis.
Pathogenesis
Various theories have been proposed to explain the pathogenesis of atherosclerosis from different perspectives. In recent years, the most widely accepted theory suggests that atherosclerosis is an inflammatory disease initiated by endothelial injury (either structural or functional).
As early as 1856, the German pathologist Rudolf Virchow proposed the idea that atherosclerosis is an inflammatory condition of the arterial intima. In 1999, Professor Russell Ross from the Washington University School of Medicine explicitly described atherosclerosis as an inflammatory disease in his response-to-injury hypothesis, emphasizing that its development is consistently accompanied by inflammatory reactions.
The normal arterial wall is lined by a single layer of endothelial cells, which serves as a critical barrier between blood and tissue. Endothelial cells have antithrombotic properties, helping to maintain blood fluidity. They synthesize and secrete various vasoactive substances, such as nitric oxide (NO), endothelin, and prostacyclin, which regulate vascular smooth muscle contraction and relaxation. Endothelial cells also secrete cytokines that influence the proliferation and migration of various cells and regulate platelet and leukocyte adhesion.
Atherosclerosis is a process of vascular injury involving interactions between vascular wall cells and blood cells under the influence of inflammatory and proliferative factors. Various pro-inflammatory stimuli, such as pathogens (e.g., Chlamydia pneumoniae, herpes viruses), chemical agents (e.g., oxidized LDL-C, angiotensin II, aldosterone, nicotine, advanced glycation end products), and physical factors (e.g., shear stress from blood flow), can cause persistent endothelial injury. This triggers the endothelial expression of adhesion molecules, such as P-selectin and vascular cell adhesion molecule-1 (VCAM-1), which mediate the adhesion of circulating monocytes and lymphocytes to the endothelium and their subsequent migration into the intima.
Within the intima, monocytes differentiate into macrophages, which engulf oxidized LDL-C via scavenger receptors, transforming into foam cells and forming the earliest atherosclerotic lesion, the fatty streak. These inflammatory cells synthesize and secrete numerous cytokines and pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), tumor necrosis factor-alpha (TNF-α), and interleukin-1 (IL-1), which promote plaque growth and inflammatory responses. T lymphocytes that enter the intima recognize antigens (e.g., modified lipoproteins) presented by macrophages and dendritic cells, becoming activated and producing pro-atherogenic cytokines such as interferon-gamma (IFN-γ), TNF, and lymphotoxins. These cytokines further recruit inflammatory cells, amplifying the inflammatory cascade.
Simultaneously, under the influence of PDGF and FGF, smooth muscle cells migrate from the media to the intima, proliferate, and engulf lipids, becoming another important source of foam cells. Additionally, smooth muscle cells proliferate significantly under the influence of fibroblast-mediated factors, synthesizing and secreting collagen, proteoglycans, and elastin, which form the extracellular matrix of the plaque. Through these mechanisms, fatty streaks evolve into fibro-fatty lesions and fibrous plaques.
In later stages, the apoptosis and necrosis of inflammatory cells release matrix metalloproteinases (MMPs), which degrade the collagen in the fibrous cap of the plaque, thinning the cap and increasing the risk of plaque rupture and thrombosis. Clinical studies have confirmed this inflammatory hypothesis of atherosclerosis. For example, the monoclonal antibody canakinumab, which targets IL-1β, has been shown to reduce cardiovascular events in coronary artery disease patients without lowering lipid levels, providing further evidence for the role of inflammation in atherosclerosis.
Pathological anatomy and pathophysiology
Atherosclerosis primarily affects large elastic arteries (e.g., the aorta) and medium-sized muscular arteries in the systemic circulation, with the coronary arteries and cerebral arteries being the most involved. Other arteries, such as those in the limbs, renal arteries, and mesenteric arteries, are less frequently affected, with lower extremity arteries more commonly involved than upper extremity arteries. Pulmonary arteries are rarely affected. It is common for arteries of multiple tissues and organs to be simultaneously involved.
Figure 1 Schematic diagram of arterial wall structure
The normal arterial wall consists of three layers: the intima, media, and adventitia. In atherosclerosis, three types of lesions sequentially develop: fatty dots and streaks, atheromatous and fibrous plaques, and complex lesions. The American Heart Association (AHA) classifies the progression of these lesions into six types:
Type I: Fatty dots
Small yellow dots appear in the arterial intima, representing localized accumulation of foam cells formed by macrophages containing lipid droplets.
Type II: Fatty streaks
Yellow streaks are visible in the arterial intima, consisting of layers of macrophages containing lipid droplets. Smooth muscle cells containing lipid droplets and infiltrating T lymphocytes are also observed in the intima.
Type III: Intermediate lesions
Extracellular lipid droplets accumulate between the intima and the smooth muscle layer of the media, forming a lipid core, though a lipid pool has not yet developed.
Type IV: Atheromatous plaques
Extensive lipid accumulation forms a lipid pool, disrupting the structure of the intima and deforming the arterial wall.
Type V: Fibroatheromatous plaques
This is the hallmark lesion of atherosclerosis, characterized by white plaques protruding into the arterial lumen, causing luminal narrowing. The surface of the plaque is covered by a fibrous cap overlying the lipid pool, replacing the damaged intima. The lesion may extend into the media, damaging the arterial wall, and may be accompanied by secondary changes such as fibrosis, degeneration, and necrosis.
Type VI: Complex lesions
These severe lesions are characterized by complications such as hemorrhage, necrosis, ulceration, calcification, and mural thrombosis. Atheromatous plaques can rupture at the surface of the intima, forming atheromatous ulcers. The ruptured atheromatous material can enter the bloodstream and become emboli.
Recent advancements in coronary imaging, particularly intravascular ultrasound (IVUS) and optical coherence tomography (OCT), have provided direct and detailed insights into the characteristics of plaques in different types of coronary artery disease. Clinically, atherosclerotic plaques can be broadly categorized into two types:
- Stable plaques
- Unstable (vulnerable) plaques
Stable plaques
These plaques have a thick fibrous cap and a smaller lipid core, making them less prone to rupture.
Unstable (vulnerable) plaques
These plaques have a thin fibrous cap and a larger lipid core, making them more likely to rupture. The rupture of unstable plaques is the primary cause of acute ischemic cardiovascular events. Other factors contributing to plaque instability include hemodynamic changes, stress, and inflammatory responses, with inflammation playing a critical role in plaque stability and rupture. Plaque instability reflects an imbalance between the mechanical strength of the fibrous cap and the forces that damage it.
When a plaque ruptures, tissue factor and platelet-activating factor are released, causing rapid platelet aggregation and forming a white thrombus. Simultaneously, the rupture triggers the release of large amounts of inflammatory factors, upregulates procoagulant substances, and promotes the synthesis of plasminogen activator inhibitor-1 (PAI-1), exacerbating thrombosis. This process can lead to the formation of a red thrombus. Thrombosis can acutely occlude the vessel, resulting in severe and persistent ischemia of the affected organ.
Figure 2 Development and progression of atherosclerosis
A. Schematic diagram of atherosclerotic plaque structure showing the fibrous cap of the plaque and the lipid pool it covers.
B. Schematic diagram of cross-sectional vascular structure during the progression of atherosclerosis, dark black areas represent thrombus and calcification, light black areas represent fatty streaks, lipid core, and lipid pool, and fine black dots represent the fibrous cap.
Figure 3 Transmission electron micrograph of aortic atherosclerotic plaque (×4,800)
The image shows foam cells derived from smooth muscle, with cytoplasm filled with lipid droplets.
Over time, atherosclerosis weakens the elasticity and increases the fragility of the affected arteries. The arterial lumen gradually narrows or becomes completely occluded. In some cases, the artery may dilate, forming an aneurysm. Depending on the affected artery and the development of collateral circulation, atherosclerosis can lead to dysfunction of the entire circulatory system or specific organs.
Reduced elasticity of the aortic wall
During cardiac systole, the aortic wall relies on its elasticity to accommodate the blood ejected from the heart, buffering the increase in systolic pressure. When the elasticity of the aortic wall decreases, this buffering effect is diminished, leading to an increase in systolic pressure, a decrease in diastolic pressure, and a widened pulse pressure. In case of aortic aneurysm, the arterial wall is replaced by fibrous tissue, losing both its elasticity and structural integrity, and bulging outward.
Narrowing or occlusion of visceral or limb arteries
When collateral circulation is insufficient to compensate, blood supply to organs and tissues is impaired, resulting in ischemia, necrosis, or fibrosis.
Atherosclerosis progresses slowly. Fatty streaks can develop as early as adolescence, with significant lesions and luminal narrowing appearing in middle age, leading to symptoms of organ ischemia. In some cases, unstable plaques progress rapidly and are prone to rupture, causing acute ischemic events. However, increasing evidence suggests that the progression of atherosclerosis is not entirely irreversible. Early-stage atherosclerotic lesions can partially regress with aggressive management and treatment of risk factors over time.
Clinical manifestations
The clinical manifestations of atherosclerosis are primarily related to the symptoms arising from the involvement of specific organs.
Aortic atherosclerosis
Most cases are asymptomatic. Extensive atherosclerotic lesions in the aorta may lead to reduced aortic elasticity, presenting with elevated systolic blood pressure and widened pulse pressure. On x-ray imaging, the aortic arch may appear prominent and displaced upward and to the left, with patchy or arcuate calcification visible. Aortic atherosclerosis can lead to the formation of aortic aneurysms or the development of aortic dissection.
Coronary artery atherosclerosis
This will be discussed in detail in coronary atherosclerotic heart disease.
Cerebrovascular atherosclerosis
The most affected arteries are the internal carotid artery, basilar artery, and vertebral artery. The internal carotid artery at its entry point into the brain is a frequent site of involvement, with lesions often concentrated at vascular bifurcations. Atherosclerotic plaques can cause vascular stenosis, cerebral hypoperfusion, local thrombosis, or plaque rupture and embolization, leading to cerebral infarction and other cerebrovascular events. Chronic cerebral ischemia over time can result in brain atrophy, potentially progressing to vascular dementia.
Renal artery atherosclerosis
This can cause refractory hypertension. In individuals over 55 years old who suddenly develop hypertension, renal artery atherosclerosis should be considered. Renal artery thrombosis may result in flank pain, oliguria, and fever. Chronic renal ischemia can lead to renal atrophy and eventually renal failure.
Mesenteric artery atherosclerosis
This may present with symptoms such as indigestion, reduced intestinal motility, constipation, and abdominal pain. Thrombosis in these arteries can cause severe abdominal pain, abdominal distension, and fever. Intestinal wall necrosis may result in bloody stools, paralytic ileus, and shock.
Peripheral artery atherosclerosis
This is more common in the arteries of the lower extremities. Impaired blood flow can cause symptoms such as coldness, numbness, and the classic symptom of intermittent claudication, namely, calf pain, numbness, or cramping during walking that resolves with rest but recurs with further walking. In severe cases, persistent pain may occur, along with weakened or absent pulses in the lower extremity arteries, especially the dorsalis pedis artery. Complete arterial occlusion can result in gangrene.
Laboratory tests
Currently, there is a lack of sensitive and specific diagnostic methods for the early detection of atherosclerosis. The diagnosis of atherosclerotic lesions involves morphological assessment and functional assessment.
Morphological assessment includes determining the location, extent, and severity of the lesions.
Functional assessment evaluates whether the atherosclerotic lesions are causing organ ischemia.
A combined evaluation of morphology and function helps guide treatment planning, including indications and methods for revascularization (either interventional or surgical).
Ultrasound can detect plaques in superficial arteries, such as the carotid and lower extremity arteries. Doppler ultrasound is useful for assessing blood flow.
X-ray imaging may reveal a widened aorta, a prominent aortic arch, or arterial wall calcification.
CT angiography (CTA) and magnetic resonance angiography (MRA) provide non-invasive imaging of atherosclerotic lesions.
Functional methods combined with non-invasive imaging, such as CT-derived fractional flow reserve (CT-FFR), can assess the degree of organ ischemia.
Evidence of myocardial ischemia or characteristic changes on electrocardiography (ECG), echocardiography, radionuclide imaging, or stress testing can aid in the diagnosis of coronary atherosclerotic heart disease.
Selective angiography can reveal arterial stenosis or aneurysmal lesions. When combined with intravascular imaging techniques and invasive functional assessments, it provides a comprehensive understanding of the morphology and function of the lesions, making it one of the most important diagnostic tools for atherosclerosis.
Patients with atherosclerosis should also be monitored for abnormalities in glucose and lipid metabolism.
Diagnosis and differential diagnosis
When atherosclerosis progresses to the stage of organ ischemia or necrosis, diagnosis is generally straightforward. However, early diagnosis is challenging. For individuals with risk factors for atherosclerosis, screening for atherosclerotic plaques using ultrasound or other non-invasive imaging techniques is recommended to guide early prevention and intervention. In older patients with dyslipidemia, vascular stenotic or dilated lesions, or calcification detected by x-ray, ultrasound, or angiography, atherosclerosis should be considered as the primary diagnosis.
Aortic changes and aneurysms caused by atherosclerosis need to be differentiated from syphilitic aortitis, aortic aneurysms, and mediastinal tumors. Other conditions such as Takayasu arteritis, Kawasaki disease, and certain autoimmune diseases can also cause arterial stenosis or dilation and should be distinguished from atherosclerosis. When ischemic or infarct-related symptoms appear in specific organs, other causes of arterial lumen narrowing or occlusion should also be considered.
Prognosis
The prognosis of atherosclerosis depends on the location, severity, and progression of vascular stenosis, as well as the extent of organ damage and the presence of complications. Atherosclerosis involving critical arteries supplying the heart, brain, or kidneys is associated with poor outcomes.
Prevention
The primary goal is to actively prevent the occurrence of atherosclerosis. If it has already developed, treatment should focus on halting disease progression and, where possible, achieving regression. For patients with complications, prompt intervention is necessary to prevent further deterioration and prolong life.
General preventive measures
Active control of risk factors
This includes addressing conditions associated with atherosclerosis, such as hypertension, diabetes, dyslipidemia, and obesity.
Healthy diet
Total caloric intake should be controlled to maintain a normal body weight, defined as a BMI of 18.5-24 kg/m2. Alternatively, waist circumference can be used as a measure, with ≥80 cm for females and ≥85 cm for males considered excessive.
Overweight or obese individuals should reduce daily caloric intake, limit cholesterol consumption, and restrict alcohol and sugary foods.
Patients with hypertension or heart failure should also moderately limit salt intake.
Appropriate physical activity and exercise
Engaging in regular physical activity and exercise can help prevent obesity, regulate blood glucose and lipid metabolism, control blood pressure, and enhance cardiovascular function.
Exercise intensity should be tailored to individual physical condition, activity habits, and cardiac function, ensuring it does not place excessive strain on the heart or cause discomfort.
Typically, 150 minutes of moderate exercise per week (e.g., 30 minutes per day, 5 days a week) is recommended. Exercise should be gradual and not overly strenuous.
Work-life balance
Overexertion and emotional stress should be avoided. Proper balance between work and rest should be ensured, and adequate sleep is necessary.
Smoking cessation and limited alcohol consumption are advised.
Treatment
The primary goals of treatment are to regulate blood lipids, prevent thrombosis, and comprehensively control risk factors (e.g., lowering blood pressure, controlling blood glucose). For patients with target organ ischemia, anti-ischemic drugs and organ-protective medications are used.
Lipid-lowering medications
LDL-C (low-density lipoprotein cholesterol) is the primary target for lipid-lowering therapy. Treatment goals are determined based on the patient's risk stratification. Statins are the first-line drugs for reducing cholesterol. If statin monotherapy is insufficient or not tolerated, combination therapy with cholesterol absorption inhibitors, PCSK9 inhibitors (proprotein convertase subtilisin/kexin type 9 inhibitors), or small interfering RNA (siRNA) drugs targeting PCSK9 protein synthesis can be used. For patients with significantly elevated triglycerides (TG), fibrates or high-dose omega-3 fatty acids (fish oil) can be considered.
Antiplatelet drugs
These medications prevent thrombosis by inhibiting platelet adhesion and aggregation, thereby reducing the progression of vascular occlusive lesions. They are used to prevent arterial thrombosis and embolism.
Common oral antiplatelet drugs include aspirin, clopidogrel, prasugrel, ticagrelor, indobufen, and cilostazol. Intravenous options include abciximab, tirofiban, and eptifibatide.
The choice of single or combination therapy depends on the patient's risk of ischemic events.
Thrombolytic and anticoagulant drugs
For patients with arterial thrombosis causing significant stenosis or occlusion, thrombolytic agents, such as streptokinase, urokinase, alteplase (rt-PA), reteplase (r-PA), tenecteplase (TNK-tPA), and prourokinase, can be used.
Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparin, bivalirudin, and fondaparinux.
Oral anticoagulants include warfarin and novel oral anticoagulants (NOACs).
Interventional and surgical procedures
For stenotic or occluded arteries, particularly in the coronary, renal, and peripheral arteries, revascularization through interventional or surgical methods can be performed to restore arterial blood flow.