Atherosclerosis

Atherosclerosis is a chronic disease of large and medium-sized arteries in which lipids, inflammatory cells, fibrous tissue and, later, calcium accumulate in the arterial intima to form plaques. The plaques narrow or weaken the vessel and can rupture or trigger clots. The disease develops silently over decades and usually causes no symptoms until a vessel is significantly obstructed or a plaque breaks open. It is the main pathological basis of cardiovascular disease and of most ischemic stroke, and it remains the leading cause of cardiovascular morbidity and death worldwide. Its importance lies both in its public-health burden and in its role as a model for how lipid metabolism, immune responses and vessel-wall biology interact in a single chronic disorder.

The entry explains what the disease is and how it differs from the broader term arteriosclerosis, and it describes the normal structure of the arterial wall that plaques invade. It then follows the disease through its stages: how risk factors and genetics set the stage, how lipoproteins are retained in the intima, how monocytes, smooth muscle cells and T and B lymphocytes shape the lesion, and how plaques become unstable and cause clinical events. Later sections cover classification, clinical presentation, diagnosis and imaging, prevention and treatment, the history of the field from nineteenth-century pathology to modern lipid and inflammation research, and the questions that remain contested.

Definition and Terminology

Working definition

Pathologists regard atherosclerosis as an inflammatory disease secondary to lesions in the intimal layer, and its complications arise mainly from narrowing or blockage of the arterial lumen. The lesion is a plaque, or atheroma, that builds up in the intima of large and medium-sized arteries and contains a lipid-rich core, a fibrous covering and inflammatory cells such as macrophages. Because the process is chronic, the plaques lead to narrowing and hardening of arteries, which restricts the blood and oxygen supply to vital organs over years or decades.

Etymology and origin of the term

The name combines two Greek roots. Athere is usually rendered as gruel or porridge, a reference to the soft, fatty material at the centre of the lesion, while skleros means hard. Together they describe a hardening that follows the accumulation of this paste-like deposit. In 1904 Marchand coined the term atherosclerosis, although the date is not uniform in the literature: one historical account attributes Marchand's proposal to 1940 and argues that the word was meant to replace "atheroma" ( athéré means gruel or porridge and sclerosis signifies hardening). The chronology of the term therefore deserves cautious handling.

Distinguishing related terms

Arteriosclerosis is the broader, older term, meaning hardening of the arteries in general. In classic pathology textbooks it has been treated as an umbrella for three lesions: atherosclerosis, arteriolosclerosis and Mönckeberg medial calcific sclerosis. Arteriolosclerosis refers to thickening of arterioles, particularly in association with systemic arterial hypertension, so it concerns small vessels rather than the large arteries where plaques develop. Mönckeberg sclerosis, by contrast, is a calcification of the vessel wall's muscular layer. Arteriosclerosis differs from atherosclerosis in that there is no intimal lipid deposition or inflammation. Monckeberg sclerosis is not an obstructive process.

George Pickering's 1963 lecture on the confusion between these terms tried to separate them by mechanism: he described atherosclerosis as an inflammatory process linked to oxidized LDL in the intima and media, and arteriosclerosis as a functional loss of large-artery elasticity. Despite this effort, usage remains inconsistent. Many clinical and lay sources still treat the words as near-synonyms; one reference notes that the two terms are often used synonymously, and a 2020 review describes the four terms as sometimes treated as synonyms even though they describe different concepts.

Lesion and clinical disease

It is useful to separate the anatomical lesion from the clinical illness. The atheroma is the pathological structure itself, whereas atherosclerotic disease is the set of ischemic syndromes that arise from it. A plaque can remain silent for many years. Symptoms typically appear when the lesion may produce stenosis (narrowing) or occlusion (closure) of the arterial lumen, or when it ruptures and may cause blood clots. Which clinical syndrome results depends on the vascular bed involved, so the same underlying process can present as coronary artery disease, ischemic stroke or limb ischemia.

Why the disease is considered systemic

Plaques are focal and unevenly distributed. They concentrate in regions of disturbed blood flow, such as branch points and curved segments, and the aorta, coronary, carotid, and iliac arteries are most frequently affected. Nevertheless, the disease is classed as systemic because the drivers act throughout the circulation: lipoproteins, circulating inflammatory signals and systemic risk factors, including hypertension, diabetes and smoking, reach every arterial segment. A person with a stable plaque in one artery may therefore carry lesions elsewhere, and the clinical consequences of disease depend heavily on which vascular territory is affected and whether an individual lesion becomes unstable.

Normal Structure of the Arterial Wall

Layers of the wall

Large and medium arteries are built from three concentric layers. The innermost layer, the intima, is an inner tunica intima consisting of endothelial cells and subendothelial extracellular matrix (ECM). Below it, the media is the thickest layer in most arteries. In muscular arteries it is mainly made of smooth muscle cells, whereas in elastic arteries such as the aorta, there are many layers of elastin with smooth muscle cells between the layers. The internal and external elastic laminae mark the boundaries of the media, with the intima sitting on the inner one and the adventitia on the outer one The media is separated from the adventitia by a prominent elastic layer, the external elastic lamina. The innermost layer of the artery wall is the tunica intima, which is separated from the media by the internal elastic lamina.

The outermost adventitia is composed of collagenous connective tissue populated by fibroblasts. The adventitia can also contain the lymphatic and nerve plexi and a network of finely lined blood vessels called the vaso vasorum. Because the wall of a large artery is too thick for diffusion from the lumen to supply its cells, the vasa vasorum matter. The vasa vasorum supplies blood and nourishment to the tunica adventitia and outer parts of the tunica media, as these layers are too thick to be nourished merely by diffusion from blood in the lumen. In the largest vessels, the network extends almost to the intima, but pressure within the wall limits how far it can perfuse inward Due to higher radial and circumferential pressures within the vessel wall layers closer to the main lumen of the artery, vasa vasorum externa cannot perfuse these regions of the vessel wall. The inner intima therefore depends largely on the blood in the lumen, which has implications for how circulating lipoproteins reach it.

Endothelial barrier function, nitric oxide and vascular tone

The endothelium is a single cell layer that controls exchange between blood and wall. Its selectivity is imperfect: lipoproteins of up to about 70 nm can pass through an intact endothelium by transcytosis, which allows apolipoprotein B-containing particles such as LDL to enter the subendothelial space. Endothelial cells also release nitric oxide (NO), a short-lived gas that diffuses into adjacent smooth muscle cells, activates guanylate cyclase, and relaxes the wall, thereby helping set vascular tone and blood pressure. Vasoconstriction and vasodilation are additionally modulated by nerves Both vasoconstriction and vasodilation are partially regulated by nerves (nervi vasorum).. In atherosusceptible regions, the endothelium shows reduced production of nitric oxide (NO), increased leukocyte adhesion, and permeability, as well as other atheroprone phenotypes. Loss of NO signalling and increased permeability are therefore early features of the disease, not just consequences of established plaque.

Hemodynamic forces and focal localization

Blood flow exerts a tangential frictional force on the endothelium, known as shear stress. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Under laminar conditions, the endothelium is exposed to steady, unidirectional drag. Disturbed flow at bifurcations and curves instead produces flow separation, recirculation and reattachment, with oscillating forward and reverse components and time-averaged shear close to zero oscillatory flow, where time-averaged fluctuations in shear stress are very low or zero due to forward-reverse flow cycles and disrupted flows, which exhibit regions of flow separation, recirculation and reattachment.

These flow patterns change gene expression. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. Endothelial cells at branches and curvatures also show higher proliferative and mitotic rates than those in the straight segment of the vascular tree. Together, these effects explain why lesions cluster at branch points, bifurcations and the outer curves of the aortic arch rather than being spread evenly along the tree.

Extracellular matrix and lipoprotein retention

The intima's matrix contains collagen, elastin and proteoglycans, and proteoglycans are the component most directly responsible for trapping lipoproteins. Proteoglycans are built from a core protein with one or more glycosaminoglycan chains, and the endothelial glycocalyx is a surface layer rich in such molecules. PGs, the main component of the extracellular matrix, form a tight and negatively charged network. Because apolipoprotein B is charged, LDL binds to this network through ionic interactions. LDL electrostatic interactions with decorin and biglycan in the valve leaflets and vascular wall is a major source of LDL retention. Retention has consequences beyond holding particles in place. Retention of LDL by intima proteoglycans appears to increase the residence time needed for their structural, hydrolytic and oxidative modification.

Matrix composition also varies with location. At branch points, the absence of a luminal elastin barrier and presence of a dense collagen/proteoglycan matrix contributes to increased retention of LDL. Some lipoprotein subfractions bind more strongly than others; compared with LDL(+), LDL(−) presents increased binding affinity to arterial PGs, the main component of the subendothelial extracellular matrix. Conversely, HDL can reduce retention, partly through its lipid-free apolipoprotein A-I, which has been shown to inhibit LDL binding to proteoglycans HDL inhibits LDL binding to PGs through an interaction with its main apolipoprotein, APOA1. These matrix-level interactions set up the subsequent events of endothelial activation and inflammation described in later sections.

Epidemiology and Global Burden

Most of the global cardiovascular disease (CVD) burden is driven by atherosclerotic lesions, so population estimates for CVD are the usual way to gauge the scale of the problem. Estimates for 2021 put annual cardiovascular deaths at close to 19.4 million, and roughly 612 million people were living with CVD worldwide. In 2021, there were approximately 227.8 million IHD cases and 100.5 million stroke cases, making them the most prevalent forms of CVD. Ischemic stroke alone accounted for about 3.6 million deaths and 70.4 million disability-adjusted life years (DALYs) in 2021. These figures come from the Global Burden of Disease Study (GBD), which is the main source for comparisons across countries.

The burden is unevenly distributed. Almost 80% of global CVD cases now occur in low- and middle-income countries, where ageing and urbanization have accelerated the increase in the burden. Income patterns have also shifted over time. Cardiovascular mortality fell globally between 1990 and 2010, with important differences by GDP per capita; in 1990, IHD mortality was positively associated with national income, and higher-income countries had higher rates than lower-income countries. Later analyses found that high-income countries were able to reduce the contribution of high BMI, blood pressure, glucose and cholesterol over the past two decades, whereas lower- and middle-income countries showed rising mortality attributable to high BMI and glucose. Regional differences remain large. An earlier cross-country review reported that age-standardized mortality ranged from 9 per 100,000 per year in Qatar to 138 in Russia.

Sex and age also shape the pattern. In China's GBD 2021 analysis, age-standardized IHD rates were higher among males, and stroke followed the same direction, whereas lower extremity peripheral artery disease showed a higher burden in females. Among people aged 15 to 39, IHD is more common than ischemic stroke: the global age-standardized incidence of IHD in 2021 was approximately three times higher than that of ischemic stroke, and from 1990 to 2021, incidence and prevalence of IHD increased significantly in this age group.

Trends over the past several decades show a split between rates and counts. Age-standardized rates have generally fallen. For ischemic stroke, the age-standardized incidence rate shows a declining trend compared to 1990, yet the absolute number of deaths increased from 2.04 million in 1990 to 3.29 million in 2019. The recent decline has also slowed: downward trends across most CVD subtypes were attenuated in the recent decade, particularly for incidence and prevalence. Projections for 2050 suggest that ischaemic heart disease will remain the leading cause of cardiovascular deaths, at about 20 million. Age-standardized prevalence is expected to remain relatively constant, while age-standardized mortality and DALYs are projected to fall substantially.

The estimates have important limitations. GBD results are modelled rather than counted directly, and they are reported with 95% uncertainty intervals. Values also change between editions: the 2026 AHA update notes that slightly different estimates reflect improvements in demography and population estimation, statistical and geospatial modeling methods, and the addition of nearly 3000 new data sources. Underlying data quality is uneven. Differences in disease classification and recording between jurisdictions, along with inequitable access to diagnostic services, can produce apparent differences in burden that do not reflect true disease frequency. Data gaps are especially serious in poorer settings: trends in most low- and middle-income countries have been hard to study because CT and MRI scanners, needed to differentiate stroke subtypes, are not widespread.

Prevalence and life expectancy are linked, though the connection is mostly inferred from trend data rather than tested directly across risk profiles. Better survival keeps people in the prevalent pool for longer. In one analysis, the limited decline in age-standardized CVD prevalence is likely an impact of small reductions in incidence, concurrent with continued marked declines in CVD mortality (and thus improving survival). Improvements in treatment after diagnosis also explain part of the fall in age-standardized mortality, as the fall in age-standardized cardiovascular mortality reflects the improvement in medical care following diagnosis. Population ageing pushes the other way: future healthcare systems can expect a rapid rise in crude cardiovascular mortality, driven by the ageing global populace. Risk profile matters as well. In the Chinese analysis, metabolic risks had the largest population-attributable fraction, which indicates that the mix of metabolic and hypertension-related exposures in a population affects how much disease that population carries at a given life expectancy.

Risk Factors and Genetic Susceptibility

Non-modifiable factors

Age is the dominant background risk. Lesions accumulate over decades, so clinical events cluster in later life. Male sex confers earlier onset: Women experience their first acute MI on average 9 years later than men. The protective difference narrows after menopause, when the loss of estrogen is associated with rising LDL cholesterol and a loss of the relative advantage women previously held. A family history of premature coronary disease in first-degree relatives also signals elevated risk, both through shared environment and through inherited variation.

Some inherited conditions produce risk that is far larger than the common polygenic background. Heterozygous familial hypercholesterolemia is an inherited genetic disorder that causes dangerously high cholesterol levels, which can lead to heart disease, MI, or stroke at an early age if left untreated. Affected individuals carry lifelong exposure to elevated apolipoprotein B-containing particles, which is why the condition is the clearest monogenic model of lipid-driven atherosclerosis.

Modifiable metabolic and lifestyle factors

The INTERHEART case-control study, which enrolled 15,152 cases and 14,820 matched controls across 52 countries, provides the most comprehensive estimate of modifiable exposures. Nine risk factors, including smoking, raised ApoB/ApoA1 ratio, hypertension, diabetes, abdominal obesity, psychosocial factors, daily fruits and vegetables, and regular physical activity collectively accounted for 90% of the population attributable risk (PAR) in men and 94% of the PAR in women. The associations were consistent across ethnic groups and geographic regions.

The individual odds ratios reported in that study were substantial. The apolipoprotein B to apolipoprotein A1 ratio showed the strongest association, with an odds ratio of 3.25 for the top versus lowest quintile. Current smoking carried an odds ratio of 2.87, a history of hypertension 1.91, and diabetes 2.37. Elevated LDL cholesterol acts through the same lipoprotein pathway described in the initiation section, whereas the other factors act on the vessel wall through hemodynamic stress, oxidant load, and metabolic dysregulation.

Lipoprotein(a) is a separate, largely genetically determined particle. It is a low-density lipoprotein (LDL)-like particle characterized by a covalently bound apolipoprotein(a) molecule and its blood levels are predominantly determined by genetic factors. According to current guidelines, Lp(a) levels higher than 50 mg/dL are regarded as a cardiovascular risk-increasing factor. Because it is inherited and largely unaffected by diet, it is considered an independent causal risk factor; in a large U.S. pooled cohort, Lp(a) is a particularly strong predictor of ASCVD risk in persons with DM, with a nearly 2-fold increased risk of ASCVD events in persons with Lp(a) levels at or above the 90th percentile.

Hypertension, diabetes mellitus (including type 2 diabetes), and central obesity also raise risk through insulin resistance, dyslipidemia and chronic low-grade inflammation, so they are better understood as clustered metabolic conditions than as independent exposures.

Genetic susceptibility and genome-wide association studies

Heritable influences on coronary disease are substantial. Estimates of narrow-sense heritability for CAD range from 40% to 60%. Large genome-wide association study (GWAS) efforts have since identified hundreds of loci: Large-scale genome-wide association studies (GWAS) have now identified over 240 loci associated with CAD across multiple ancestries.

The chromosome 9p21 locus is the most replicated of these signals. Since publication of the first genome-wide association studies (GWAS) of coronary artery disease (CAD) in 2007, Chr9p21 has emerged as the most significant risk locus associated with this frequent disease. The risk haplotype spans a non-coding stretch rather than a gene: The risk locus contains no protein coding genes or known microRNAs. The nearest genes, approximately 100 kb upstream of the risk locus, are a pair of tumor suppressor genes (cyclin dependent kinase inhibitors, CDKN2A and CDKN2B). The locus overlaps a long non-coding RNA called ANRIL, which has been proposed to regulate expression of these neighbouring genes. Its effect appears to be distinct from classical risk pathways, since Chr9p21 lacks associations with common cardiovascular risk factors, such as lipids and hypertension, indicating that the locus exerts its effect through a completely novel mechanism. The per-allele effect is modest; in a collaborative meta-analysis of angiographically defined cases, the association between 9p21 and CAD had a pooled odds ratio of 1.31. A 2025 preprint nominates the gene MTAP as the likely effector, but the causal transcript and cell type remain debated.

Polygenic risk scores (PRS) aggregate the small effects of many variants, weighted by effect sizes from GWAS, into a single estimate per person. In research they are used to stratify populations, test for gene–environment interaction, and examine whether genetic risk is independent of measured risk factors. Their predictive accuracy falls markedly when they are applied to ancestries different from those in which the weights were derived, which limits their current clinical use.

Interaction and combined risk

Risk factors do not simply add together. The interaction of lipoprotein(a) with other factors illustrates this clearly. In a familial CAD cohort, marked elevations in risk were seen when high Lp(a) was combined with hypertension, high H(e), or low bilirubin, with observed relative odds for these combinations greater than the product of each risk factor alone. The effect of Lp(a) also depended on lipid status: high Lp(a) was found to greatly increase risk only if the total/HDL cholesterol ratio was at least mildly elevated, an effect exaggerated by other risk factors. More recent work reports that when elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect has been reported. Evidence in patients with well-controlled LDL remains conflicting.

The mechanistic basis for this synergy lies in the vessel wall. Elevated apolipoprotein B particles supply more substrate for retention and oxidation in the intima. Hypertension increases circumferential stress and disturbs endothelial shear, which increases adhesion molecule expression. Smoking and hyperglycaemia increase oxidant and advanced glycation burdens that impair nitric oxide signalling and amplify inflammatory activation. Obesity adds adipokine-driven inflammation. Because each factor attacks a different arm of the initiating process, their combined effect on the endothelium exceeds the sum of their separate effects.

Combined risk estimation has therefore moved towards multivariable tools. A simplified score derived from INTERHEART data was developed and validated for MI risk which is applicable to an international population. Individual prediction nevertheless remains imprecise, because genetic susceptibility, lipoprotein(a) and environmental exposures are only partly captured by conventional clinical variables.

Initiation: Endothelial Dysfunction and Lipoprotein Retention

Endothelial activation and dysfunction

The earliest changes are focal. They appear where the endothelial cells that line the intima sit under abnormal mechanical load. Disturbed flow often occurs at arterial branch points and curvatures, resulting in a high susceptibility to atherosclerosis. Endothelial cells act as mechanosensors. In straight arterial segments, unidirectional pulsatile shear stress supports endothelial homeostasis, whereas oscillatory shear at bends and bifurcations induces a local inflammatory environment, promoting site-specific initiation and progression of atherosclerosis. Reciprocating, low-magnitude shear shifts endothelial gene expression toward pro-atherogenic programs, while sustained laminar flow keeps protective genes active.

Endothelium in these atheroprone regions changes its function as well as its gene expression. It shows reduced production of nitric oxide (NO), increased leukocyte adhesion, and permeability, and it is more permeable to plasma macromolecules, which lets lipoproteins pass into the wall. Hyperlipidemia adds to this stress. In hypercholesterolemic animals, both VCAM-1 and ICAM-1 are upregulated over early foam cell lesions, particularly at the periphery. Oxidative stress contributes in parallel. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) damage lipids, proteins and carbohydrates, causing lipid peroxidation and LDL oxidation. Oxidized LDL, in turn, promotes endothelial dysfunction, foam cell formation, monocyte chemotaxis, smooth muscle cell proliferation and migration, and platelet activation, which feeds back on the endothelium.

Upregulation of adhesion molecules

Once activated, endothelial cells display adhesion molecules that catch passing leukocytes. Capture happens in stages. Loose adhesion is mediated by selectins and their interactions with cell surface carbohydrates. Most notably, VCAM-1 binds very late activation antigen-4, ICAM-1 binds lymphocyte function-associated antigen-1, and E-selectin binds cell surface carbohydrates. Selectins slow the cells so that the integrin-based molecules can secure firm arrest.

VCAM-1 is the most consequential of these in lesion formation. Normal human arteries show little VCAM-1, whereas focal segments of the endothelium were positive for ICAM-1 and E-selectin. Expression is strongly mechanosensitive: low shear stress upregulates VCAM-1 and downregulates ICAM-1, whereas both molecules are upregulated when shear stress is elevated. Experimental blockade gives the clearest picture of their weight. In animal models, blocking or eliminating P-selectin, VCAM-1 or α4β1 integrin reduces atherosclerotic lesion formation by more than 50%. Smaller effects are seen by manipulating E-selectin, ICAM-1 or the JAM family of adhesion molecules. Native LDL can also raise ICAM-1 expression on cultured endothelial cells and boost monocyte adhesion, so adhesion-molecule induction is not restricted to oxidized particles.

Entry and retention of apolipoprotein B-containing lipoproteins

Apolipoprotein B-containing particles enter the intima because the endothelial barrier is leaky in these regions. Lipoproteins up to 70 nm in diameter can cross an intact endothelium through transcytosis, so LDL (18–25 nm) and IDL (25–35 nm) are easily taken up by the arterial wall. Once inside, they are held there. In the arterial wall, LDL binds ionically to proteoglycans in the extracellular matrix. The binding is mediated mainly by the apoB100 protein, which interacts with negatively charged proteoglycan glycosaminoglycan chains. Williams and Tabas proposed that subendothelial retention of atherogenic lipoproteins is the central pathogenic process in atherosclerosis, and this idea underlies the response-to-retention model. In that model, the earliest intimal change is diffuse thickening that contains proteoglycans but no lipid or macrophages, and this "preretention" zone then accumulates lipoproteins before macrophages arrive.

Retention is self-reinforcing and can become irreversible. Binding to proteoglycans makes LDL more susceptible to oxidation and aggregation, which promotes foam cell formation and a proinflammatory response. Aggregation and fusion of particles in the subendothelium can make them too large to leave the wall again. Smaller, denser LDL particles bind proteoglycans more strongly but are also more prone to oxidative modification.

Oxidative and enzymatic modification of retained lipoproteins

Native LDL is not considered strongly atherogenic by itself. Native LDL is not atherogenic and needs to be oxidatively modified, particularly apoB, to instigate the disease while it stays in the subendothelium bound to glycosaminoglycans. Among the various modifications that LDL undergoes in the wall, oxidation represents a primary modification. The effect of oxidation on proteoglycan binding is not uniform in the literature. Some studies report that mild oxidation of LDL increased its binding to CS proteoglycans and to HS proteoglycans, whereas heavy oxidation reduced LDL binding to CS to levels lower than that of native LDL, while other work reports reduced binding after oxidation of apoB100 lysine residues.

Enzymatic changes run alongside oxidation. Secretory sphingomyelinase hydrolyzes LDL and increases particle aggregation and affinity for proteoglycans, and lipoprotein lipase can act as a bridge between lipoproteins and proteoglycans. Oxidized lipids formed in this way are pro-inflammatory. They activate endothelial cells further and set up the chemotactic signals that bring monocytes into the intima, which is the transition to the next stage of lesion development.

Monocyte Recruitment and Foam Cell Formation

Once apolipoprotein B-containing lipoproteins have been retained in the intima, the wall starts to recruit circulating monocytes. The key signal is the CC chemokine MCP-1 (CCL2). MCP-1 becomes fixed to the luminal surface of the endothelium by binding proteoglycans, and its interaction with CCR2 on mononuclear cells drives their passage into the subendothelial space (is immobilized on the luminal surface of the endothelium through binding with proteoglycans. Interactions between MCP-1 and its receptor CCR2, expressed on mononuclear cells, mediate mononuclear cell (Mo) recruitment into the subendothelial space.). Genetic experiments support a causal role. Deleting the MCP-1 gene in LDL-receptor-deficient mice, or in mice overexpressing human apolipoprotein B, reduced diet-induced lesions and macrophage accumulation without changing lipoprotein metabolism, and loss of CCR2 produced similar protection in apoE-null mice (Deletion of the MCP-1 gene in LDL receptor deficient mice and in animals overexpressing human apolipoprotein B protected from the development of diet-induced atherosclerosis, dramatically reducing macrophage recruitment in the aortic wall without altering lipoprotein metabolism. In addition, deletion of CCR2, the only functional MCP-1 receptor, attenuated macrophage accumulation in atherosclerotic lesions). These data separate the recruitment step from lipid levels themselves. Chemokines of the chemokine family, including CCL2, are therefore best seen as the switch that converts retained lipid into an inflammatory lesion. Recruited monocytes that enter the intima differentiate into macrophages, which become the dominant lipid-handling cell type of early plaques.

Scavenger Receptor Uptake and Foam Cell Formation

Intimal macrophages take up modified lipoproteins, chiefly oxidized LDL, mainly through scavenger receptors rather than through the LDL receptor. In vitro, CD36 and SR-A account for 75% to 90% of ox-LDL internalization by macrophages, whereas other SRs cannot compensate for their absence. The uptake is poorly controlled. The LDL receptor is suppressed when a cell is loaded with cholesterol, but CD36 and SR-A are not shut down in the same way, so intracellular cholesterol keeps rising. Lesional expression of these receptors is further reinforced. Exposure to ox-LDL induces CD36 transcription via the PPAR-γ pathway, establishing a positive feedback loop that enhances foam cell formation. Stored cholesterol is esterified by ACAT1 into cholesteryl ester droplets, which give the cell its foamy appearance (The FC is then re-esterified to CE by the enzyme acyl cholesterol acyl transferase (ACAT1) leading to ER stress and thus cell apoptosis). Accumulated lipid-laden macrophages and foam cells form the early fatty streak, the first visible lesion of the disease.

The receptor system is also redundant. In mice lacking SR-A and CD36 on an apoE-deficient background, aortic root atherosclerosis showed no decrease in lesion area or in vivo foam cell formation when compared to Apoe−/− mice. The authors suggested a partial, region-specific role. Other receptors, including LOX-1, may therefore help maintain lipid uptake when CD36 or SR-A is absent.

Why Foam Cells Persist in the Lesion

Foam cells stay in the intima for several reasons. First, lipid uptake outpaces efflux. Cholesterol export depends on ABCA1 and ABCG1, which move cholesterol to apolipoprotein A-I and HDL respectively. Their expression is driven by liver X receptor activation (ABCA1 and ABCG1 expression upregulation by liganded LXR promotes cholesterol efflux of FC to apoA-I and HDL, respectively.). In atherosclerosis, cholesterol uptake is increased due to endothelial leakage and scavenger receptor upregulation while cholesterol efflux is downregulated. Second, CD36 signalling itself works against migration. This CD36-initiated signaling cascade inhibits macrophage migration and promotes foam cell formation. Cells that are loaded with lipid and cannot leave therefore accumulate. Third, the failure of clearance described below means that dying foam cells are not replaced by healthy cells.

Efferocytosis, the phagocytic removal of apoptotic cells, is central here. In early lesions, monocyte-derived macrophages recruited into developing atherosclerotic lesions initially display efficient efferocytosis and temper inflammatory responses, processes that restrict plaque progression. As the plaque grows, that capacity declines. Macrophages undergo cellular reprogramming that reduces efferocytic capacity, which results in post-apoptotic necrosis of apoptotic cells and inflammation. Signals that normally mark dying cells for removal, such as phosphatidylserine recognised by MerTK and MFG-E8, are reduced in advanced lesions, so apoptotic cells are no longer cleared in time (Apoptotic cells regulate their clearance by balancing "eat-me" signals, such as phosphatidylserine recognized by MFGE8 and MerTK, and "don't-eat-me" signals, most notably CD47). Mouse studies show that loss of MerTK increases apoptotic cell accumulation and plaque necrosis (Necrotic cores result from the combination of macrophage apoptosis and defective phagocytic clearance (efferocytosis) of these apoptotic cells.). Failed efferocytosis therefore does more than enlarge the lesion: it turns foam cells into the lipid-rich necrotic core that later determines plaque vulnerability.

Taken together, the recruitment, uptake and retention steps form a self-reinforcing cycle. Chemokines bring in more monocytes, scavenger receptors load them with cholesterol, impaired efflux and migration keep them in place, and defective efferocytosis causes them to die within the intima. The balance between these processes, rather than any single step, determines how fast the fatty streak progresses.

Smooth Muscle Cell Phenotypic Switching and Matrix Remodeling

From contractile cell to synthetic cell

Medial smooth muscle cells (SMCs) normally keep the vessel wall's tone and diameter through a contractile gene program. In plaques, the cells that reach the intima have lost much of that program. Reviews describe a sequence of dedifferentiation, migration and, in some cases, transdifferentiation into other cell types, and the changes appear to be driven by altered flow and the local microenvironment (This switching is characterized by VSMC dedifferentiation, migration, and transdifferentiation into other cell types.; under atherosclerotic stimuli, VSMCs respond to altered blood flow and microenvironment changes by downregulating contractile markers and switching their phenotype.).

Older models treated the switch as a simple two-state transition between a contractile and a synthetic form. Lineage tracing and single-cell sequencing have complicated that picture. Lesional SMC descendants show many intermediate states, including macrophage-like, foam-cell-like, mesenchymal stem cell-like, myofibroblast-like and osteochondral-like phenotypes (VSMCs downregulate contraction markers during atherosclerosis while adopting other phenotypes, including macrophage-like, foam cell, mesenchymal stem-like, myofibroblast-like, and osteochondral-like phenotypes.). Lineage studies also indicate that plaque SMCs expand from a small founder pool. Multicolour tracing suggests that VSMC contribution to atherosclerotic plaques is oligoclonal, whereby one or very few pre-existing VSMCs give rise to all lesional VSMCs. A proliferative, SCA1- and VCAM1-positive intermediate population has been proposed as the source of many of the downstream lesional states (computational trajectory analysis predicted that a fibrous cap-related VSMC state arises from a previously described plastic, intermediate VSMC population expressing SCA1 and VCAM1.).

Proliferation, migration and matrix synthesis

Once in the intima, SMCs multiply and secrete matrix. Their accumulation is not uniformly protective. SMCs can move into the fibrous cap and possibly stabilize the plaque, or they can accumulate in the lipid-rich core and possibly amplify inflammation (SMCs can migrate into the fibrous cap, presumably stabilizing the plaque, or accumulate within the lesional core, possibly accelerating vascular inflammation.). The fibrous cap is built from SMC-derived cells that produce the fibrillar collagens and elastin needed for tensile strength (The fibrous cap is rich in VSMCs, many of which express typical contractile VSMC markers, as well as ECM components such as fibrillar collagens and elastin.). A recent single-cell study identified a cap-associated state that co-expresses contractile genes, matrix genes and NOTCH3, and that appears to be enriched in caps rather than lipid cores (a disease-specific VSMC state co-expressing contractile genes with extracellular matrix (ECM) components (including fibrillar collagens and elastin) and NOTCH3, which are associated with fibrous cap formation.).

The number of cap SMCs is a practical determinant of stability. Plaques with thicker caps built from layers of SMCs are generally regarded as more stable, whereas plaques with large necrotic cores and thin, SMC-poor caps are regarded as vulnerable (Plaques with less lipid content and thicker fibrous caps comprised of layers of SMCs are generally considered stable and at lower risk of rupture and adverse clinical outcomes. Those with larger necrotic cores and thinner caps with reduced SMC content are considered unstable or vulnerable.). Cap SMCs are also prone to death: thinning is associated with decreased SMC proliferation and increased SMC apoptosis (Thinning of the fibrous cap occurs through decreased VSMC proliferation and increased VSMC apoptosis.).

Protease-driven degradation of the cap

Matrix breakdown is the counterpart of matrix synthesis. Plaque rupture is best understood as a failure of the intimal extracellular matrix, and the destruction must be carried out by proteases, most importantly matrix metalloproteinases (MMPs) (Plaque rupture results from net destruction of the intimal extracellular matrix (ECM), which must be driven by proteases.). MMPs are capable of cleaving collagens, gelatins and elastin, and different family members degrade different substrates (The matrix metalloproteinases co-expressed in the hierarchical clustering target a broad spectrum of substrates, including collagens (MMP1, MMP8, and MMP13), gelatins (MMP9), elastins (MMP12), and fibronectin (MMP7).).

The effects of MMPs are context-dependent. In one mouse study, MMP-9 was linked to greater stability, while MMP-12 promoted destabilization (In a mouse model of plaque vulnerability, MMP9 was associated with greater plaque stability, while MMP7 attenuated VSMC content and MMP12 promoted destabilization.). MMP-2 illustrates the same ambiguity: it can accumulate SMCs in the cap, yet its gelatin-degrading activity can weaken the matrix (MMP-2 was found to enhance plaque stability by accumulating VSMCs into the fibrous cap of atherosclerotic apolipoprotein-E knockout mice. However, the gelatin-binding site in the MMP-2 catalytic domain made MMP-2 capable of degrading gelatins in the extracellular matrix (ECM) of the fibrous cap enclosing the atherosclerotic plaque, hence promoting plaque instability.). Macrophages are an important source of these enzymes. Human macrophages in culture were shown to break down collagen in cap tissue in an MMP-dependent way, and the effect was blocked by an MMP inhibitor (human monocyte-derived macrophages were shown to induce collagen breakdown in fibrous caps of human atherosclerotic plaques associated with cellular expression and zymographic evidence of MMP activity; no evidence of collagen breakdown was found in the presence of an MMP inhibitor.). Rupture tends to occur at the shoulder of the plaque, where active macrophages accumulate (Rupture of those plaques occurs mainly in their shoulder, where active macrophages accumulate and apoptosis may occur.).

Transdifferentiation and the unresolved question of lineage

The most contested part of this section is the fate of SMC descendants that lose SMC markers. Genetic tracing shows that some SMC progeny stop expressing SMC markers and acquire macrophage-like features, and in advanced plaques a subset of SMCs can become macrophage-like or foam cells (a subset of these cells in the advanced atherosclerotic plaques can differentiate into macrophage-like cells or foam cells. Genetic lineage tracing studies demonstrate that some descendants of SMCs may no longer express SMC markers and convert to macrophage-like cells.). Whether this conversion is stable is disputed. One dual-recombinase study found that a fraction of SMC-derived macrophage-like cells re-adopted an SMC identity in the fibrous cap, where they contributed to fibroblast-like and pericyte-like cells (a subset of these cells re-adopted the SMC lineage in the fibrous cap, contributing to fibroblasts and pericytes in the plaque.). Other groups have not reached the same conclusion, and the marker-based classification itself is imperfect. Cells that express both SMC and macrophage markers have been observed in human lesions, which leaves open whether SMCs have acquired macrophage features or macrophages have acquired SMC features (Andreeva et al. reported the presence of cells that express both SM α-actin and the macrophage marker CD68 within human atherosclerotic lesions. What is unclear is whether these are SMCs that have activated macrophage markers or macrophages that have activated SMC markers?).

Because of these ambiguities, the overall contribution of SMCs to foam cells, osteochondrogenic cells and inflammatory cells in plaques is still being defined. Reviews note that the molecular controls on SMC switching in vivo are far less well understood than in cultured cells (Although much is known regarding factors and mechanisms that control SMC phenotypic plasticity in cultured cells, our knowledge of the mechanisms controlling SMC phenotypic switching in vivo is far from complete.). The traditional view that SMCs are uniformly protective, forming a cap that shields the core from rupture, has therefore been revised, but the balance between stabilizing and destabilizing SMC behaviour in individual patients remains unresolved.

Adaptive and Innate Immune Responses in the Lesion

CD4+ T-cell subsets

Lesional T cells include several CD4+ subsets whose effects on the plaque often point in opposite directions. An inflammatory adaptive response, driven mainly by T helper 1 (Th1) cells but also involving Th17 and Th2 cells and B cells, develops as regulatory T (Treg) cell numbers fall. Human histology supports the pro-atherogenic role of Th1 cells: Th1 CD4+ T-cells predominated in advanced plaques, whereas Th2 cytokines including IL-4 and IL-5 were rarely detected. Recruitment of these cells appears to depend on chemokine signaling through CXCR3. The main effector of this subset is interferon-γ. It weakens the fibrous cap by blocking smooth muscle cell collagen synthesis, and it keeps macrophages and dendritic cells activated, which sustains the Th1 response (IFN-γ recruits VSMCs to impede collagen synthesis; enhanced macrophage and DC activity supports the pathogenic Th1 response).

Th17 cells, which secrete IL-17A, IL-17F, IL-22 and IL-23 in addition to the signature cytokine IL-17A, are less well understood. IL-17 from Th17 cells can promote atherosclerosis, although few studies report that it also stabilizes plaques. One proposed explanation for the stabilizing effect is that IL-17A promotes collagen synthesis, whereas IFN-γ suppresses it. Th17 differentiation is favored by IL-1, IL-6, and IL-23, all of which are known to be expressed in atherosclerotic lesions. In plaques, the boundary between subsets is not fixed. A substantial proportion of FOXP3+ T cells co-express the Th17 transcription factor RORγt or the Th1 factor T-bet, and a recent review argues that the plaque microenvironment can push Tregs toward instability and Th17-like behaviour (the inflammatory milieu within the plaque actively promotes Treg destabilization and Th17 differentiation).

Regulatory T cells and tolerance

Regulatory T cells act as the main brake on this response. They restrain Th1- and Th17-mediated proinflammatory responses and reduce the antigen-presenting function of dendritic cells. They are one of the mechanisms by which the immune system maintains tolerance to self-antigens. In plaques, however, their numbers are decreased and their function may be impaired. Experimental work suggests that inducing tolerance, for example through oral or mucosal routes, could strengthen this protective arm (induction of oral and mucosal tolerance may protect against atherosclerosis). Some of the evidence on the roles of Th2 and Th17 cells is still disputed: the role of Th2 and Th17 cells in atherogenesis is still debated.

B cells and antibodies

B cells have a dual role that depends on their subset. Antibodies against oxidation-specific epitopes on LDL and on apoptotic debris are central to this role. Natural antibodies, particularly those targeting oxidized epitopes abundant in modified lipoproteins and cellular debris, are a distinctive feature of atherosclerosis. B1a and marginal-zone B cells produce natural IgM that neutralizes these signals: innate B cells, including B-1 cells and marginal zone B cells, provide atheroprotection through production of IgM to oxidation-specific epitopes. IgM that binds oxidized LDL can also block its uptake by scavenger receptors on macrophages, which limits foam cell formation (IgM binds oxidized LDL and so reduces its binding to scavenger receptors on monocytes and macrophages; proinflammatory cytokine secretion and foam cell formation decline). In humans, an inverse correlation has been reported between OSE-specific IgM and atherosclerotic burden and cardiovascular outcomes. By contrast, most experimental evidence supports a pro-atherogenic role for B2 cells, and IgG antibodies against oxidized LDL show variable association with vascular risk. Findings from mouse studies remain inconsistent overall: the possible role of B cells in atherosclerosis has been studied extensively in experimental models with inconsistent results.

Cytokine networks

Cytokines link the innate and adaptive arms of the response. Pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-12, TNF-α, and interferon-γ, play a pivotal role in perpetuating the inflammatory intimal environment. Their effects overlap. IL-18 induces the cytokines GM-CSF, TNF-α, IL-1β, IL-6 and the chemokine IL-8, and macrophage activation by IFN-γ leads to the production of other proinflammatory cytokines like TNF-α and IL-6, oxygen radicals, and metalloproteinases. IL-6 is a particularly important example. Vascular smooth muscle cells contribute significantly to IL-6 production, and in mice, administration of IL-6 to ApoE-deficient mice augmented plaque burden without altering cholesterolemia. Results from IL-6 deficiency models have been mixed, however. Among the others, TNF upregulates the expression of adhesion molecules (ICAM-1, VCAM-1) and monocyte chemoattractant protein-1 (MCP-1), while IL-10 and TGF-β are generally regarded as anti-atherogenic (anti-atherogenic IL-1ra, IL-9, IL-10 and IL-11 versus pro-atherogenic IL-1, IL-2, IL-6 and IL-18).

Innate–adaptive interplay

Innate and adaptive immunity are closely linked in the lesion. Adaptive responses develop against a range of potential antigens presented to effector T lymphocytes by antigen-presenting cells, especially dendritic cells. Innate recognition is equally important: oxidation-specific epitopes act as danger signals recognized by pattern recognition receptors of innate immunity, including scavenger receptors, innate effector proteins, and natural IgM antibodies. The pro-atherogenic Th1 pathway is therefore fed by innate cells, and the protective natural IgM response is driven by innate-like B cells. Current evidence favours a model in which the balance between effector and regulatory arms, rather than any single cell type, determines whether the lesion grows or becomes stable.

Cell Death, Senescence and the Necrotic Core

Cell death shapes how a lesion changes from a quiescent deposit into a dangerous plaque. Apoptotic macrophages and smooth muscle cells are normally cleared quickly from most tissues, but in the diseased arterial wall this clearance fails. The process at fault is efferocytosis, the recognition and engulfment of dying cells by phagocytes. Although apoptotic cells are cleared quickly in almost all other tissue beds, their removal appears to be significantly impaired in the diseased blood vessel. Emerging evidence indicates that this phenomenon is caused by a defect in efferocytosis. As plaques advance, the uncleared cells undergo secondary necrosis, forming a highly inflammatory "necrotic core". Some authors argue that the decisive problem is clearance rather than the rate of cell death, because efficient phagocytes would normally keep pace with apoptosis (efferocytosis operates at high efficiency, so exuberant plaque apoptosis is unlikely to be the leading cause of necrosis).

Mechanisms of defective clearance

Several molecular steps contribute to this failure. Surface receptors that bind dying cells are lost or altered. In one study, cleavage of the MerTK receptor was shown to be a causal factor in the development of necrotic cores in atherosclerotic lesions. Macrophages in plaques also become reprogrammed as lesions grow, reducing their efferocytic capacity, which results in post-apoptotic necrosis of apoptotic cells and inflammation.

The consequences extend beyond the size of the core. Efferocytosis normally helps macrophages export cholesterol: externalized phosphatidylserine on apoptotic cells upregulates ABCA1 in macrophages, which promotes the efflux of cholesterol to ApoA1, whereas necrotic cells do not elicit this response. Defective clearance therefore also sustains foam cell accumulation. The necrotic core itself is harmful: it activates harmful inflammatory processes in lesions, is a source of tissue-disrupting proteases and procoagulant molecules, and adds physical stress to the overlying fibrous cap.

Endoplasmic reticulum stress and the unfolded protein response

The endoplasmic reticulum (ER) is the site of folding for secreted and membrane proteins, and in lesional cells its capacity is overwhelmed. Accumulation of misfolded proteins activates the unfolded protein response (UPR): misfolded protein accumulation in the ER lumen causes BiP/GRP78 to dissociate from three sensors, PERK, IRE1 and ATF6, initiating a signaling cascade. The UPR is initially protective, but when it is prolonged it switches to cell death. The UPR is chronically activated in lesional cells, particularly advanced lesional macrophages and endothelial cells, driven by oxidative stress, oxysterols, and high intracellular cholesterol and saturated fatty acids. Persistent signalling through the transcription factor CHOP is a major route to apoptosis, and apoptosis with enhanced CHOP expression has been demonstrated in human atherosclerotic lesions and in ApoE-deficient mice. Because ER stress alone may be insufficient, a "two-hit" model has been proposed in which a second signal, such as a pattern-recognition receptor ligand, pushes stressed macrophages into death (ER stress in lesional macrophages may be induced by low doses of stress agents, which in turn induces macrophage apoptosis). Oxidative protein folding in the ER also generates reactive oxygen species, which contribute to the oxidative load on the cell (oxidative protein folding is associated with increased reactive oxygen species production that may lead to extensive oxidative stress and cell apoptosis). Mitochondrial oxidative damage, including membrane injury and release of mitochondrial DNA and cytochrome c into the cytosol, reinforces the same death pathways and the inflammatory signalling that follows them.

Cellular senescence and the secretory phenotype

Senescent cells are a second source of harm. They stop dividing permanently while remaining metabolically active. Senescent cells from plaques lack proliferation, overexpress p16INK4A, p53 and p21, and show increased senescence-associated beta-galactosidase activity. Their most important effect is the senescence-associated secretory phenotype (SASP), in which they secrete increased amounts of inflammatory cytokines, chemokines and matrix-degrading proteases.

Senescence occurs in several vascular cell types. Senescent smooth muscle cells promote plaque calcification and enlargement of the necrotic core via SASP. Senescent endothelial cells show matrix metalloproteinases, which are key SASP components, degrading the extracellular matrix of the fibrous cap and contributing to a vulnerable plaque phenotype. Senescent macrophages also weaken the clearance system: the burden of senescent cells contributes to an environment that biases macrophages away from clearing cholesterol from vessel walls. SASP activity is context-dependent, with beneficial effects during acute activation and deleterious consequences when it is chronically sustained.

Downstream outcomes: regression, calcification and leakage

Dying cells and their debris set the stage for several late features. Lipid-lowering can reduce the supply of new lipid and allow some regression of lesions, but a necrotic core with unresolved efferocytosis defects limits how much can be reversed; the extent of regression is discussed in the controversies section. Calcification often begins in association with dead cell debris and matrix vesicles from smooth muscle cells, and it ranges from microcalcifications to large plates whose mechanical effects differ (see the morphology section). Dying cells and chronic inflammation also stimulate the growth of fragile neovessels from the vasa vasorum, whose leakage causes intraplaque hemorrhage, an important source of further cell death and lesion expansion.

Emerging Systemic and Molecular Modulators

Several recently characterized influences act on atherosclerosis from outside the arterial wall or through intracellular signalling networks. Some are systemic, such as blood-cell mutations and gut-derived metabolites. Others act within lesional cells, such as innate sensing pathways and non-coding RNAs. Most of the mechanistic evidence comes from mouse models, and its relevance to human disease is still being tested.

Clonal hematopoiesis of indeterminate potential (CHIP) arises when a blood stem cell acquires a somatic mutation and its progeny expand, without a diagnosable blood cancer. The most frequently involved genes include DNMT3A, TET2, ASXL1 and JAK2. In a 2017 study of human cohorts, carriers of mutations in DNMT3A, TET2 or ASXL1 had roughly 1.7 to 2.0 times the risk of incident coronary heart disease, while the JAK2 V617F mutation was associated with about 12 times the risk. Carriers with CHIP also had a fourfold higher risk of myocardial infarction in early-onset case-control cohorts. Experimental work supports a causal role. Mice receiving TET2-deficient hematopoietic cells develop larger plaques, and their TET2-deficient macrophages secrete more interleukin-1β through the NLRP3 inflammasome. An NLRP3 inhibitor was more protective in these animals than in controls. JAK2-mutant macrophages instead activate the AIM2 inflammasome and show DNA replication stress. Clinically, no therapy has yet been shown to reduce cardiovascular risk specifically in CHIP. Many clinicians therefore use clone size and driver gene to decide how intensively to lower LDL cholesterol.

Several intracellular signalling pathways shape lesion biology, but their effects depend on cell type, stage and context, so they can be protective or harmful. Transforming growth factor-β (TGF-β) promotes smooth muscle cell differentiation and collagen synthesis, which helps maintain the fibrous cap, but it can also drive fibrosis and calcification. Mitogen-activated protein kinase (MAPK) cascades, including ERK, p38 and JNK, are activated by oxidized LDL and by cytokines, and they increase adhesion molecule expression and inflammatory gene transcription. The PI3K/Akt/mTOR axis regulates lipid uptake, proliferation and autophagy. Its activation in macrophages has been linked to impaired clearance of dead cells and to necrotic core growth, and mTOR inhibition reduces lesions in animal studies. JAK-STAT signalling transmits signals from interleukin-6 and interferon-γ, and STAT1 is generally considered pro-atherogenic. The role of STAT3 is less clear. JAK inhibitors are being examined in part because of their effects on these cytokine pathways.

The cGAS-STING pathway has emerged as an innate sensor that links cell damage to inflammation. Cytoplasmic DNA, including mitochondrial DNA released from stressed or dying cells, activates cGAS, which produces a second messenger that engages STING. STING then signals through TBK1, IRF3 and NF-κB to induce cytokines such as TNF-α, CCL2 and type I interferons. In atherosclerotic mice, macrophages accumulate damaged DNA and show increased STING expression. Genetic deletion of STING, or pharmacological inhibition, reduced macrophage clustering and inflammatory responses in plaques. Oxidized LDL can trigger mitochondrial DNA release in macrophages, and some risk factors, including hypertension, diabetes and smoking, may enhance this pathway. Alongside STING, macrophage immunometabolism is an active area of study. Oxidized lipids and cytokines reprogram energy metabolism in macrophages, altering glycolysis, mitochondrial respiration and the production of signalling metabolites. These changes influence whether macrophages become proinflammatory or resolve inflammation. Oxidative DNA damage, produced by reactive oxygen species in lesional cells, is also thought to contribute to this inflammatory loop, although its precise causal weight remains uncertain.

Gut microbiota affect atherosclerosis through their metabolites. The best-studied example is trimethylamine N-oxide (TMAO). Gut bacteria convert dietary choline, phosphatidylcholine, carnitine and betaine into trimethylamine, which the liver oxidizes to TMAO. Circulating TMAO levels correlate with cardiovascular risk in many studies, and TMAO has been reported to promote endothelial dysfunction, macrophage foam cell formation, NLRP3 inflammasome activation and platelet hyperreactivity. However, some studies have found no relationship between TMAO concentrations and lesion progression, and it remains unclear whether TMAO is a causal driver or a marker of diet and kidney function. Other microbial products, such as short-chain fatty acids and bacterial components that can translocate across the intestinal barrier, are also being investigated.

Non-coding RNAs and epigenetic modifications add another regulatory layer. MicroRNAs (miRNAs) fine-tune gene expression in endothelial cells, smooth muscle cells and macrophages. For example, miR-33 suppresses cholesterol efflux genes such as ABCA1, and endothelial miRNAs influence vascular inflammation. Some circulating miRNAs have been proposed as biomarkers. TMAO-associated miRNA networks, including miR-21-5p, miR-126 and the miR-17/92 cluster, have been reported in recent reviews. Epigenetic regulation, including DNA methylation and histone modification, can alter inflammatory gene expression in monocytes and vascular cells, and some of these changes appear to persist after risk factors are modified. Whether such marks are cause or consequence of lesion development is still under investigation.

Plaque Morphology, Calcification and Classification

Histopathological classification

The earliest formal scheme came from the World Health Organization in 1958, which described a sequence running from fatty streak through atheroma and fibrous plaque to complicated lesions. In the mid-1990s, the American Heart Association (AHA) recommended a new morphological classification based on six lesion types (later expanded to roman numerals I to VIII), built on histology and the work of Stary and colleagues. Virmani and colleagues later proposed a more streamlined system that focuses on the state of the fibrous cap. Their 2000 scheme recognized seven categories, including intimal xanthoma, pathological intimal thickening, thin-cap fibroatheroma, calcified nodule and fibrocalcific plaque. A modified framework also dropped the numeric AHA types V and VI, because those categories did not capture the three distinct routes to coronary thrombosis: rupture, erosion and calcified nodule. Stary himself stressed that lesion progression does not necessarily occur in a single direction or in a strictly sequential manner, so the categories describe states rather than fixed stages.

Early, intermediate and advanced lesions

Early lesions are composed mainly of lipid-laden foam cells. Type I lesions contain isolated macrophages and macrophage-derived foam cells, while fatty streaks (type II) show more foam cell layers and intracellular lipid, and do not protrude substantially into the lumen. Intermediate lesions add further inflammatory cells and extracellular lipid deposits. The first advanced stage is the atheroma, in which a confluent lipid core forms without a perceptible fibrous cap. The fibroatheroma, the most clinically important category, is defined by a lipid-rich necrotic core encapsulated by collagen-rich fibrous tissue. Such lesions can result in significant luminal narrowing and are prone to surface disruption, thrombosis and calcification. Lesions dominated by calcium or by fibrous tissue with little lipid form the calcified and fibrotic end-stage categories.

Microcalcification and macrocalcification

Calcium deposits are usually divided by size: micro- and macrocalcification are categorized based on nodules of <50 μm and ≥50 μm, respectively, although no universal convention exists. Microcalcifications begin as small crystals of hydroxyapatite that coalesce into organised areas. They are thought to arise as a healing response to intense necrotic inflammation, and they are consistently associated with culprit and unstable plaque phenotypes. Biomechanically, microcalcifications concentrate stress in the fibrous cap. In one micro-CT study, peak circumferential stress rose from 210 kPa to 396 kPa when microcalcifications were present, while 300 kPa is regarded as the minimum threshold for rupture. Dense macrocalcification, by contrast, forms sheets that stabilize the plaque, effectively walling off the necrotic core from the lumen. This paradox explains why coronary calcium scores, which long seemed to predict harm, are now interpreted with more nuance. Some biomechanical work still suggests that large calcium masses may themselves raise stress, so the debate is not fully settled. Clinically, conventional CT cannot resolve microcalcifications, whereas 18F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification.

Neovascularization and intraplaque hemorrhage

As plaques thicken, the tissue becomes hypoxic because of the high oxygen demand of macrophages, which triggers intraplaque neovascularization by upregulation of pro-angiogenic factors, such as vascular endothelial growth factors (VEGFs). These new vessels grow mainly from the adventitial vasa vasorum and carry inflammatory cells and lipoproteins into the lesion, which intensifies the lipid and inflammatory environment. The neovessels are structurally abnormal, with disorganized morphology, the loss of basement membrane and pericytes, and abnormal wall permeability. Because they are fragile, they are regarded as the leading cause of intraplaque hemorrhage. Hemorrhage contributes to growth and destabilization, and it is considered an independent predictor of intraplaque hemorrhage and plaque rupture. Imaging of the vasa vasorum is therefore being explored as an early marker of vulnerability. Postmortem studies had already linked rupture-prone plaques to a thin fibrous cap, high lipid content, increased numbers of inflammatory cells, and extensive adventitial and intimal neovascularization.

Plaque Instability, Rupture and Thrombosis

Most ischemic events in atherosclerosis happen not because a lesion gradually narrows the lumen, but because a plaque changes abruptly and triggers a thrombus. The concept of the vulnerable plaque, developed largely through pathology work by Renu Virmani and colleagues, describes lesions that are prone to such change. The best-defined form is the thin-cap fibroatheroma (TCFA): a fibrous cap of less than 65 µm overlying a large lipid-rich necrotic core, with dense macrophage infiltration, relatively few smooth muscle cells, and often positive (outward) vessel remodelling. TCFAs usually do not produce severe narrowing; in autopsy series they are most often found in lesions with less than 50% diameter stenosis. Because most myocardial infarctions arise in such moderate lesions, luminal stenosis alone identifies only a small share of patients at risk of acute events.

Cap thickness is a strong determinant of rupture risk. In an optical coherence tomography study of 502 patients with culprit lesions, caps of 65 µm or less were associated with markedly higher odds of rupture and of thrombosis than caps thicker than 80 µm, and caps between 65 and 80 µm carried an intermediate risk. The necrotic core contributes to the problem: its tissue factor, oxidized lipids and cellular debris are highly thrombogenic once exposed to blood.

Rupture versus erosion

Acute coronary thrombosis has two principal pathological substrates. In plaque rupture, the thin cap tears, and blood comes into contact with the necrotic core and with its inflammatory, lipid-rich material. The fibrous cap is typically heavily infiltrated by macrophages and T lymphocytes, and the lesion often contains calcification. In plaque erosion, the endothelium is lost over a fibrous or proteoglycan-rich plaque without a lipid core communicating with the lumen. Eroded lesions show fewer macrophages and T cells, few or no lipid cores, and clusters of smooth muscle cells near the thrombus, and they are less often calcified. A third mechanism, thrombosis over a calcified nodule, accounts for a small minority of cases.

The relative frequency of these mechanisms depends on the series and the population studied. Early autopsy studies from the 1990s found rupture in roughly 45–65% of sudden coronary deaths, with erosion in the remainder. A more recent summary of post-mortem data gives about 55–65% for rupture, 30–35% for erosion and 2–7% for calcified nodules. Erosion is more common in younger patients, particularly premenopausal women and people under 50, and it is more strongly associated with smoking. Erosion-related events also tend to present more often as non-ST-elevation syndromes, and the lesions are generally less bulky, with lower lipid burden and less severe narrowing.

Tissue factor, platelets and thrombus formation

Thrombus formation depends on the material exposed at the damaged surface. Plaque rupture exposes tissue factor from macrophages and foam cells, which activates the coagulation cascade and produces fibrin-rich, erythrocyte-containing "red" thrombi. Fibrillar collagen and other subendothelial matrix components also activate platelets through specific receptors, adding a platelet-rich component. Thrombi on ruptured plaques contain higher proportions of fibrin and more tissue factor than those on eroded plaques, whereas erosion typically produces platelet-rich "white" thrombi, which are more likely to embolize distally. Post-mortem comparisons have reported embolization of plaque material in a substantially larger share of erosion cases than of rupture cases. Platelet activation, aggregation and locally elevated thrombin then consolidate the clot, and a thrombus that is incompletely occlusive may be followed by healing, while a fully occlusive one produces transmural ischaemia.

From luminal narrowing to ischemic events

The clinical consequence depends on the degree of luminal obstruction and on whether the thrombus is occlusive. A thrombus that totally blocks a coronary artery typically causes ST-elevation myocardial infarction, whereas a partially occlusive thrombus, or one that embolizes into the microcirculation, is more often associated with non-ST-elevation acute coronary syndromes. Mean luminal stenosis at the site of autopsy-confirmed rupture is high (about 78%), and erosion sites are only somewhat less narrowed (about 70%), so the degree of stenosis alone does not separate the two mechanisms. Equivalent processes in carotid or intracranial arteries can produce thromboembolic ischaemic stroke, and in peripheral vessels they can cause acute limb ischaemia. The same concepts guide revascularization decisions and anti-platelet and anticoagulant therapy, which target the thrombotic rather than the purely stenotic component of disease.

Clinical Manifestations and Organ-Specific Disease

Atherosclerosis is often silent for years. Symptoms usually appear when a lesion narrows an artery substantially, or when a complication such as thrombosis, embolization or aneurysmal enlargement occurs. Many people first learn they have the disease after a heart attack or stroke. Which symptoms appear depends mainly on which vascular bed is affected, so one underlying process can present as chest pain, leg pain, a transient neurological deficit or a slow decline in kidney function.

Coronary artery disease

Atherosclerosis of the coronary arteries produces the clinical syndromes grouped as coronary heart disease. Plaques that narrow a coronary artery by more than half tend to cause predictable, exertion-induced stable angina, whereas plaques that narrow less but are unstable are more likely to rupture unpredictably. Plaque rupture is the most common mechanism of acute coronary thrombosis leading to myocardial infarction, and it is especially associated with fatal events. Plaque erosion, in which the endothelial surface is lost without a fibrous cap rupture, accounts for roughly one-third of acute coronary syndromes, and about two-thirds of non-ST-elevation infarctions. Acute coronary syndromes present with angina, dyspnea, nausea, sweating, arrhythmia or, in severe cases, shock and sudden cardiac death. Carotid plaques share a similar composition, but they usually cause harm through severe stenosis or occlusion, or by shedding platelet-rich emboli.

Cerebrovascular disease

Carotid and intracranial plaques cause stroke and transient ischemic attack (TIA). A TIA is defined by a rapidly developing neurological deficit or monocular visual loss that resolves within 24 hours, while an ischemic stroke is a deficit persisting beyond 24 hours without hemorrhage on imaging. Sudden weakness or numbness on one side, speech disturbance and vision loss are the typical warning features. Many patients with carotid disease first come to attention after a TIA or stroke rather than with earlier symptoms. Imaging studies comparing plaques in patients with TIA and those with stroke have examined intraplaque hemorrhage, lipid-rich necrotic cores and calcification, and diagnostic work-up increasingly aims to identify these features.

Peripheral artery disease, mesenteric ischemia and renal artery stenosis

In peripheral artery disease (PAD), narrowing of limb arteries most often causes intermittent claudication, which is pain or cramping in the calf, thigh or buttock during walking that eases with rest. In advanced cases, pain at rest, non-healing ulcers and gangrene develop, a pattern known as chronic limb-threatening ischemia. Many people with PAD have few or no symptoms, and the ankle-brachial index is the usual first test.

Mesenteric ischemia occurs when atherosclerosis narrows the celiac, superior mesenteric or inferior mesenteric arteries. Its hallmark is postprandial abdominal pain, which can lead to food avoidance and weight loss. Most patients with visceral stenosis are asymptomatic until a large part of the splanchnic circulation is compromised.

Renal artery stenosis reduces perfusion of the kidney and activates the renin system, producing hypertension that is difficult to control. Over time, it can reduce kidney function and contribute to chronic kidney disease. In people over about 55, narrowing of the renal arteries may progress to renal failure or malignant hypertension. An abdominal bruit heard on examination can be an early clue. Not every case is atherosclerotic, since arterial dysplasia and thrombo-embolism are alternative causes.

Aortic aneurysm

Atherosclerosis is a recognized contributor to abdominal aortic aneurysm (AAA), although aneurysms also arise from connective-tissue disorders, infection, trauma and dissection. Aneurysmal walls show infiltration by macrophages and lymphocytes, and atherosclerotic changes are frequently found alongside these inflammatory features. AAAs are usually asymptomatic, and the principal danger is rupture as the segment enlarges. Historical series reported very high mortality after rupture.

Links to chronic kidney disease

The relationship between atherosclerosis and chronic kidney disease (CKD) runs in both directions. CKD, which affects roughly 10% to 20% of adults in many countries, is a recognized independent risk factor for cardiovascular disease, and up to half of people with CKD die from it. Reduced kidney function alters the endothelium and vascular wall even when conventional risk factors are absent. In a study of 297 patients undergoing transesophageal echocardiography, CKD was associated with a higher frequency of complex thoracic aortic plaques. Cohort and nationwide data also associate CKD, and especially advanced CKD stages, with a higher risk of AAA. Shared pathways, including matrix metalloproteinases such as MMP-2 and MMP-9, are proposed to drive both aortic dilatation and renal fibrosis.

Diagnosis, Imaging and Risk Assessment

Atherosclerosis is usually found indirectly. Plaques often stay silent for decades, so clinicians combine blood markers that estimate exposure, imaging that reveals the lesion, and risk equations that guide treatment. No single test establishes the disease in an asymptomatic person, and diagnosis of its complications, such as coronary artery disease, rests on symptoms, electrocardiography, biomarkers of myocardial injury and anatomical imaging.

Laboratory assessment

The standard lipid panel reports total cholesterol, LDL cholesterol (LDL-C), HDL cholesterol and triglycerides. LDL-C is commonly calculated with the Friedewald equation, which becomes unreliable at high triglyceride levels, so direct assays or newer estimation methods are used in that setting. Apolipoprotein B and non-HDL cholesterol are increasingly reported because they better reflect the number of atherogenic particles rather than their cholesterol content.

Lipoprotein(a) is an LDL-like particle with an additional apolipoprotein(a) attached to apoB. Lp(a) is a cholesterol-like particle largely determined by genetics. Unlike traditional cholesterol markers, lifestyle changes have little impact on Lp(a) levels, and they remain relatively stable throughout life. A level of 125 nmol/L or higher is generally regarded as high-risk, and the 2026 cholesterol guidelines from 11 major heart and medical organizations recommend a single measurement for all adults. Interpretation is complicated because Lp(a) levels are decreased in the settings of severe acute phase conditions, postmenopausal hormone replacement, hyperthyroidism, and liver disease. The once-in-a-lifetime strategy is also debated: one longitudinal cohort found substantial midterm variation, and its authors argued that the recommendation should be revisited.

Systemic inflammation is assessed with high-sensitivity C-reactive protein, a nonspecific biomarker of inflammation that is typically measured when the patient is not acutely ill. Glycemic status is judged by glucose and glycated hemoglobin (HbA1c), since diabetes markedly raises risk. Markedly elevated LDL-C also prompts evaluation for familial hypercholesterolemia.

Non-invasive imaging

Coronary artery calcium (CAC) scoring uses computed tomography to quantify calcium in the coronary arteries, usually as an Agatston score. CAC as measured by the Agatston score is a strong predictor of atherosclerotic cardiovascular disease events. Its main value lies in refining risk. Its negative predictive value has a high ability to rule out clinically relevant atherosclerotic cardiovascular disease. However, a score of 0 does not permanently reclassify a person to lower risk, and periodic reassessment every 5 to 10 years remains necessary. Conversely, an elevated score can reclassify intermediate-risk individuals to high risk, which may justify preventive medication.

Computed tomography angiography (CCTA) visualizes luminal stenosis and, in newer systems, plaque composition. Guidelines for stable chest pain recommend pretest probability stratification before cardiac imaging testing such as coronary CT angiography. Ultrasonography of the carotid and peripheral arteries measures wall thickness and plaque and can be combined with the ankle-brachial index, which current guidelines describe as comparable to predictors such as C-reactive protein and the coronary calcium score. Magnetic resonance imaging, including black-blood vessel wall imaging, can characterize carotid and aortic plaques and identify lipid-rich cores and intraplaque hemorrhage, though it is used mainly in research and specialist settings.

Invasive assessment and molecular imaging

Intravascular ultrasound (IVUS) uses a catheter-mounted transducer to measure plaque burden and vessel remodeling in a coronary segment. Optical coherence tomography (OCT) uses near-infrared light at much finer resolution, which allows measurement of fibrous cap thickness; a cap thinner than about 65 μm defines a thin-cap fibroatheroma, a feature linked to rupture-prone lesions. Both methods are invasive and are chiefly used in research, procedural guidance and selected clinical decisions.

Molecular imaging aims to detect biological activity rather than anatomy. Positron emission tomography with 18F-fluorodeoxyglucose (FDG) largely reflects tracer uptake by plaque macrophages and, therefore, inflammation, with smaller contributions from other resident cell types. FDG uptake can identify patients at the highest risk of clinical events and serves as a surrogate end point in clinical trials of antiatherosclerotic therapies. Its main limitation is in the coronary arteries, where background myocardial uptake is generally greater than any signal originating from a plaque. Sodium fluoride (18F-NaF) PET, which detects microcalcification, has been reported as more sensitive at detecting atherogenic changes compared to FDG-PET in some studies, and alternative tracers such as 68Ga-DOTATATE are being tested for coronary imaging.

Risk calculators and their limits

Population risk equations, including the Framingham Risk Score, the pooled cohort equations, SCORE2 and the newer PREVENT equations, estimate ten-year event probabilities from age, sex, blood pressure, lipids, glycemia, smoking and other variables. Their discrimination is moderate. Several risk prediction models exist for asymptomatic individuals, but systematic reviews have generally found them to be of limited utility. In one validation study, adding CAC raised the C-statistic from about 0.7 to about 0.8, and in a prospective cohort the C-index for SCORE2 alone was 0.61 and rose to 0.75 when CAC was added.

Several limitations follow. Calibration varies across ethnic groups, countries and time, and equations derived in one population can misestimate risk in another. Because most events occur in people classed as low or intermediate risk, an individual's category predicts future events only probabilistically. Risk thresholds also depend on guideline choice, so the same person may be treated differently under different systems. Finally, a risk score is a snapshot; repeated assessment is needed as age, blood pressure and lipids change.

Prevention and Treatment

Treatment of atherosclerosis works on two fronts: slowing the formation and progression of lesions, and preventing the thrombotic and ischemic events that plaques cause. Most of the evidence concerns the first front, and it is strongest for lowering circulating lipoproteins. Anti-inflammatory strategies and revascularization are tested or used under narrower indications.

Lipid-lowering therapy

Statins, which inhibit HMG-CoA reductase, remain the foundation. Statins lower the LDL-C levels by 35%–60%. Their effect is partly offset by compensatory changes in cholesterol handling, including increased intestinal absorption, which is one reason combination therapy is used. Ezetimibe blocks intestinal uptake of cholesterol through the NPC1L1 transporter. In the IMPROVE-IT trial, adding ezetimibe to simvastatin reduced LDL cholesterol to 54 mg/dL compared with 69 mg/dL on statin alone, and the combination reduced cardiovascular events unequivocally, with the benefit seen in patients with diabetes and in those with prior bypass surgery.

PCSK9 inhibitors are monoclonal antibodies that block the PCSK9 protein, which normally promotes degradation of hepatic LDL receptors. Large phase 3 trials showed that both evolocumab and alirocumab produce mean reductions in LDL cholesterol of approximately 60% when added to standard statin treatment or when given alone. In the FOURIER trial, evolocumab lowered LDL cholesterol to 30 mg/dL against 90 mg/dL on statin alone. Pooled analyses of trials with achieved LDL levels below 55 mg/dL have not identified a threshold at which further lowering becomes harmful, a point that remains debated in guideline discussions.

Inclisiran is a small interfering RNA that silences hepatic PCSK9 synthesis, so it is given as an injection requiring only two doses a year after initiation. In the pooled ORION-10 and ORION-11 analysis, twice-yearly inclisiran (after initial doses at Days 1 and 90) resulted in a mean placebo-corrected LDL-C reduction from baseline to Day 510 of 51.5%. Its cardiovascular outcome trial, ORION-4, has not yet reported; the registry lists its primary completion as estimated for 2026. In the VICTORION-Challenge trial, inclisiran produced a larger LDL reduction than bempedoic acid, with higher LDL-C goal attainment [78.2% vs 20.3%].

Bempedoic acid inhibits ATP-citrate lyase, an enzyme upstream of cholesterol synthesis, and is aimed mainly at patients who cannot take statins. In the CLEAR Outcomes trial, treatment with bempedoic acid during a median follow-up of 40.6 months significantly lowered the risk of major adverse cardiovascular events, but its LDL effect is smaller, with bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) relative to placebo. Its adverse effects include a higher incidence of gout and gallstones.

Blood pressure, glucose and other risk factors

Blood pressure lowering, smoking cessation, weight reduction and the control of glycemia are central to prevention, because each acts on the same vessel-wall processes that drive lesion growth. Intensive systolic blood pressure targets have reduced cardiovascular events in trials of hypertensive adults, and sodium-glucose cotransporter-2 inhibitors and GLP-1 receptor agonists have reduced major cardiovascular events in people with type 2 diabetes. Antithrombotic therapy follows the clinical setting. Aspirin is standard after myocardial infarction, and dual antiplatelet therapy with a P2Y12 inhibitor is used after acute coronary syndromes and stenting, typically for several months. In stable coronary or peripheral disease, adding low-dose rivaroxaban to aspirin reduced events in the COMPASS trial, but at the cost of more bleeding. Routine aspirin for primary prevention in older adults is no longer generally recommended because bleeding risk offsets the benefit.

Anti-inflammatory approaches

The strongest clinical test of the inflammatory hypothesis is CANTOS, which randomized 10,061 patients with prior myocardial infarction and high-sensitivity CRP above 2 mg/L to canakinumab, a monoclonal antibody against interleukin-1β. Anti-inflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. The benefit was modest, and canakinumab was associated with a small but statistically significant risk of fatal infection, while there was no significant difference in all-cause mortality. Canakinumab has not entered routine clinical use for this indication. Colchicine, a low-cost anti-inflammatory agent, has been tested at 0.5 mg daily, and in patients with coronary disease colchicine 0.5 mg daily reliably reduces hs-CRP over and above statins. By contrast, the parallel CIRT trial of methotrexate did not reduce cardiovascular events, so the evidence for anti-inflammatory therapy is mixed and drug-specific.

Revascularization

Revascularization relieves flow-limiting stenosis but does not halt the underlying disease, so it is always combined with medical therapy. Percutaneous coronary intervention with drug-eluting stents is used for acute coronary syndromes and for stable lesions that cause symptoms or documented ischemia. Coronary artery bypass grafting is generally preferred for left main disease and for multivessel disease, particularly in patients with diabetes, where the FREEDOM trial found lower rates of death, myocardial infarction and stroke with surgery than with stenting. Carotid endarterectomy or stenting is considered for symptomatic high-grade carotid stenosis, and endovascular treatment or bypass surgery is used for limb-threatening peripheral ischemia.

Historical Development of Research

Pathologists had described the lesions of atherosclerosis in considerable detail by the nineteenth century, but their origin remained disputed. In 1856, Rudolf Virchow proposed that the lesions of atherosclerosis result from injury to the artery wall. Competing accounts held that plaques formed through the deposition of blood-borne material on the intima (the "encrustation" view) or through lipids entering the wall from the blood (the "lipid infiltration" view). For much of the following century, Virchow's injury concept was overshadowed. The theory that considered the atherosclerotic plaque as a passive fat accumulation prevailed.

The experimental turn came in the first decade of the twentieth century. Ignatowski reported that rabbits fed a diet of full-fat milk, eggs and meat soon developed pronounced atherosclerosis of the aorta. Nikolai Anitschkow and S. S. Chalatow in St Petersburg then tested individual dietary components. Whole eggs or egg yolks alone produced the effect, while egg whites alone, even in large amounts, did nothing. In 1913 Anitschkow showed that it was cholesterol alone that caused these atherosclerotic changes in the rabbit arterial intima. He described fatty streaks and advanced atheromatous plaques, and found that the amount of cholesterol uptake was directly proportional to the degree of atherosclerosis formation. His interpretation anticipated later ideas: his explanation for this observation was what modern terminology calls 'response-to-injury'.

Anitschkow's findings were slow to win acceptance. Critics argued that the rabbit responded atypically to dietary cholesterol, and Anitschkow himself proposed that high blood cholesterol was necessary but not always sufficient for atheromatous disease. General acceptance of the validity and importance of the lipid hypothesis of atherogenesis did not come until 1984. Parallel human observations supported the idea. Carl Müller described a hereditary condition with raised plasma cholesterol and premature myocardial infarction, and Adolf Windaus demonstrated cholesterol within atherosclerotic plaques (the cholesterol hypothesis gained further support from these findings). The rabbit model later proved informative for inherited disease as well, since its features strikingly resemble the cardinal features of homozygous familial hypercholesterolemia in humans.

The mechanistic basis of the lipid hypothesis was supplied by Michael Brown and Joseph Goldstein. Their work showed that human cells have low-density lipoprotein (LDL) receptors that remove cholesterol from the blood, and that LDL suppressed the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. They continued their work on the LDL receptor and eventually purified and sequenced it. Their contribution was recognized by the 1985 Nobel Prize in Physiology or Medicine "for their discoveries concerning the regulation of cholesterol metabolism." Their work also clarified why some individuals with inherited receptor defects develop severe hypercholesterolemia and early coronary disease, which links molecular biology to the epidemiological observations that had accumulated since mid-century, including the Framingham Heart Study that began in 1948 and went on to identify major risk factors such as cholesterol, blood pressure and smoking.

The shift toward a cellular and inflammatory understanding of atherosclerosis was driven largely by Russell Ross and his colleagues. In 1973, Ross and Glomset proposed the hypothesis that atherosclerosis is a 'response to injury', specifically, of injury to the vascular endothelium. The hypothesis was revised repeatedly, and one of the most significant changes in recent years has been the increasing number of recognized injurious agents, which are, of course, also 'risk factors' for atherogenesis. Later work focused on oxidation of LDL and its interaction with the endothelium as the initial injury leading to the formation of fatty streaks. Ross's framework also changed how the artery wall itself was viewed: instead of a site for passive accumulation of blood lipids, the artery wall is now seen as a living, reactive tissue capable of mounting an inflammatory response. Ross's 1999 review, "Atherosclerosis – an inflammatory disease," placed inflammation and immunity at the center of this view, and subsequent decades of research on inflammatory and macrophage-driven mechanisms built on it.

Controversies and Unresolved Questions

The relative weight of lipid-driven and inflammation-driven mechanisms is the sharpest dispute in the field. Lipid lowering is the established pillar of prevention, but the most direct clinical test of inflammation as a causal driver came from an IL-1β-blocking antibody trial. In more than 10,000 people with prior myocardial infarction and hsCRP at or above 2 mg/L, quarterly 150 mg canakinumab produced a significantly lower rate of cardiovascular events than placebo. That dose met the prespecified significance threshold, although the trial showed no significant difference in all-cause mortality. A later analysis found that patients who reached on-treatment hsCRP below 2 mg/L had fewer major adverse cardiac events, while those remaining at or above that level showed no benefit. Because this is an on-treatment subgroup analysis rather than a randomized comparison, it cannot show that lowering CRP itself is the mechanism. The open questions are which inflammatory pathways are worth targeting, whether benefit depends on patient selection, and whether the anti-inflammatory effect operates independently of lipids. Investigators have reported reduction of cardiovascular events independent of lipid levels, but the lipid and inflammatory arms remain tightly interlinked in vivo, and separating them experimentally is difficult.

Residual Cardiovascular Risk

Lowering LDL cholesterol does not remove risk. Landmark trials such as FOURIER revealed that a substantial residual risk persists even when LDL-C levels are reduced to historically unprecedented low levels. LDL cholesterol was reduced to around 30 mg/dL, and the risk of major atherosclerotic cardiovascular events fell by 15%. In established coronary disease, residual annual risk approximates 9% despite aggressive LDL-C reduction.

Candidate explanations include triglyceride-rich lipoproteins. Remnant cholesterol is carried by lipoproteins rich in cholesterol esters that are believed to have atherogenic potential similar to LDL, and its plasma concentration relates to cardiovascular risk independently of LDL cholesterol. Lipoprotein(a) and apolipoprotein B-based measures have also been proposed as better markers of residual risk: non-HDL-cholesterol and apolipoprotein B provide superior assessment of residual risk compared with LDL-C, and lipoprotein(a) remains predictive of cardiovascular events even when LDL-C levels are well controlled. In one tertiary-care cohort, nearly one-third of patients with optimal calculated LDL-C (< 70 mg/dL) exhibited high remnant cholesterol, although such discordance has not been validated as a universal treatment threshold. Non-lipid factors contribute as well. In a cohort of patients with coronary disease, moderate to advanced chronic kidney disease (stage 3–5) was an independent predictor of plaque progression. Glycaemic control matters too: in an imaging study of statin-treated patients, despite similar improvements in lipid levels, plaque regression was less pronounced in patients with high HbA1c levels.

Plaque Regression and Clinical Events

Regression is now documented by imaging, but its size and clinical meaning are less settled. The first randomized intravascular ultrasound trial of statins, from 1997, demonstrated a significant reduction in total atheroma volume at 36 months among patients treated with pravastatin compared with placebo. Later work with more patients and higher-intensity statins reported modest changes; for example, the ASTEROID study showed a 6.1% reduction in total atheroma volume at 24 months. The degree of regression tracks lipid lowering: moderate lipid lowering (LDL-C 110 mg/dl) was associated with an increase in atheroma volume, while intensively treated patients (LDL-C 79 mg/dl) showed no change in plaque burden at follow-up. Another analysis suggested that the degree of LDL-cholesterol reduction rather than the statin dose was associated with plaque regression.

The key unresolved issue is whether a smaller plaque volume translates into fewer events. Volume is an imperfect surrogate, because plaque composition is a major determinant of the tendency of atherosclerotic lesions to provoke clinical events. Observational studies have compared event rates between patients with and without volumetric regression, but such designs are confounded by treatment adherence and baseline risk, and they do not establish causality.

Model Systems and Population Representation

Much of the mechanistic knowledge comes from animal models, particularly mice lacking apolipoprotein E or the LDL receptor, which generally require high-fat diets to develop lesions. These models differ from humans in lipoprotein distribution, rarely develop the spontaneous plaque rupture and erosion seen in patients, and have limited capacity to recapitulate human lesion ageing. Agents that reduce lesions in mice have repeatedly failed to deliver equivalent benefit in clinical trials, so translational predictions remain uncertain.

Women have also been underrepresented in many clinical and mechanistic studies, and sex-specific biology, including the effects of menopause on lipid metabolism and vascular function, is incompletely characterized. Because many risk equations were derived predominantly from male cohorts, their calibration in women may be less accurate, with consequences for detection, treatment thresholds and the design of future trials.

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