How does a fatty streak develop in atherosclerosis?

How Fatty Streaks Develop in Atherosclerosis

Fatty streaks form when lipid-laden macrophages accumulate in the arterial intima, representing the earliest pathological abnormality in atherosclerosis that begins in childhood and progresses with age. 1

Initial Lipid Entry and Trapping

• LDL particles enter the arterial intima through passive molecular sieving, a process that increases proportionally with higher plasma LDL concentrations 2
• Once inside the intima, LDL particles become trapped because they are too large to penetrate the elastic laminas of the arterial media 2
• In early lesions, extracellular lipids deposit in the outer layer of pre-existing diffuse intimal thickening (DIT), colocalizing with specific proteoglycans like biglycan and decorin 3

Lipid Modification and Macrophage Recruitment

• LDL must undergo modification—particularly oxidation—before macrophages can take it up to form foam cells 2, 4
• Oxidized LDL is deposited in macrophages lining the arteries, contributing directly to foam cell formation 2
• The oxidation process makes LDL highly susceptible to uptake by cultured macrophages and exhibits chemotactic activity that attracts more inflammatory cells 4

Monocyte-to-Macrophage Transformation

• Circulating monocytes attach to endothelial cells and migrate into the subintimal space, where they transform into macrophages 2
• This process is triggered by injury to the arterial wall from cigarette smoking, hypertension, atherogenic lipoproteins, and hyperglycemia 2
• Macrophages take up cholesterol lipoproteins to initiate fatty streak formation, becoming the hallmark cells of atherosclerotic plaques 2

Foam Cell Formation

• Foam cells form when macrophages accumulate oxidized LDL, becoming filled with indigestible cholesterol droplets while triglycerides, proteins, and phospholipids are degraded 1, 2
• Unlike LDL uptake (which requires modification), triglyceride-rich lipoproteins can be taken up directly by macrophages via the VLDL receptor without modification 1
• Macrophages and foam cells in atherosclerotic plaques express lipoprotein lipase, which may stimulate further foam cell formation from triglyceride-rich lipoproteins 1, 2

Progression Pattern

• As lipid grades increase, macrophages increase in number and infiltrate toward deeper layers of the intima 3
• Fatty streaks are present in practically all individuals from every human population, with aortic fatty streaks appearing in childhood and coronary fatty streaks beginning in adolescence 5
• By ages 20-29, most persons have coronary fatty streaks of some degree, regardless of sex, race, or national origin 5

Structural Evolution

• Fatty streaks exhibit a 60% increase in intimal thickness compared to control tissue, with fat droplets in intimal cells accounting for approximately half the increase 6
• Some fatty streaks (approximately 19%) contain cholesterol clefts in the deep musculo-elastic layer, suggesting progression toward more advanced lesions 6
• Volume fractions occupied by cells in deep intima are reduced when cholesterol clefts are evident, indicating cell loss in early core regions 6

Risk Factor Relationships

• Serum total cholesterol and LDL cholesterol levels are strongly related to aortic fatty streaks, while VLDL cholesterol correlates with coronary artery fatty streaks 5
• For every 10-15 mg/dL rise in non-HDL cholesterol, an additional year of vascular "aging" occurs, demonstrating a dose-response relationship 7
• Elevated LDL cholesterol, hypertension, smoking, diabetes, and obesity are each directly linked to the presence and extent of atherosclerotic lesions in young adults aged 15-34 years 7

Clinical Pitfall to Avoid

The critical misconception is that fatty streaks are clinically benign and universally reversible. While fatty streaking is potentially reversible, evidence shows that some fatty streaks exhibit transitional features—including intimal thickening, core region formation, and cell disappearance—indicating they are progressive lesions and sites of eventual fibrous plaque development 6. This underscores why aggressive treatment of risk factors must begin early, as atherosclerotic cardiovascular disease begins in childhood and is progressive 1.