Coronary atherosclerosis

Article written and reviewed by Dr Luca Moretti

Coronary atherosclerosis is a chronic, progressive, and systemic disease of the wall of the epicardial coronary arteries, characterized by the formation within the intima of fibroatheromatous lesions resulting from the accumulation and retention of apolipoprotein B-containing lipoproteins, activation of innate and adaptive immune responses, phenotypic modification of vascular smooth muscle cells, extracellular matrix deposition, cell death, formation of a necrotic core, and, in advanced stages, calcification and arterial-wall remodeling. The disease may remain subclinical for decades, cause a progressive reduction in coronary flow reserve, or suddenly become complicated by thrombosis superimposed on a plaque, giving rise to acute coronary syndromes.

Coronary atherosclerosis must not be equated simply with the presence of an angiographic stenosis. In the early and intermediate stages, the progressive increase in plaque volume may be compensated by positive remodeling of the wall, with relative preservation of luminal caliber despite an already substantial atherosclerotic burden. A considerable proportion of the disease is therefore non-obstructive and may not be recognizable by conventional coronary angiography alone, which is essentially luminography. Coronary computed tomography angiography, intravascular ultrasound, and optical coherence tomography have profoundly changed this concept by allowing direct assessment, with different capabilities, of the arterial wall, plaque burden, and morphological lesion features.

The relationship among atherosclerosis, myocardial ischemia, and coronary syndromes is also not one-to-one. An atherosclerotic plaque may be present without causing ischemia; an intermediate anatomical stenosis may not be hemodynamically significant; diffuse disease may reduce coronary vasodilator capacity even without a single critical stenosis; and ischemia may occur without obstructive coronary atherosclerosis through microvascular dysfunction or vasospasm. Similarly, an acute coronary syndrome may arise from a plaque that caused only modest stenosis before the event when thrombosis due to rupture, superficial erosion, or, less frequently, an eruptive calcified nodule becomes superimposed on the preexisting lesion.

The contemporary concept of the disease has therefore moved beyond a purely stenotic model. Clinical risk depends on the interaction among overall atherosclerotic burden, plaque composition and biological activity, coronary anatomy, local hemodynamic conditions, systemic and local inflammation, the healing capacity of the wall, platelet and coagulation activity, characteristics of circulating blood, and the amount of myocardium supplied by the lesion. The traditional concept of a single “vulnerable plaque” has likewise progressively been replaced by the broader concepts of high-risk plaque and, above all, the high-risk patient.

Epidemiologically, the anatomical prevalence of coronary atherosclerosis does not coincide with that of ischemic heart disease because a substantial proportion of disease remains subclinical. Ischemic heart disease is nevertheless the main clinical manifestation of coronary atherosclerosis and its most useful global epidemiological indicator. According to the Global Burden of Cardiovascular Diseases and Risks 2023, approximately 239 million people worldwide had ischemic heart disease in 2023, with about 8.91 million deaths and 193 million disability-adjusted life years attributed to the disease. Ischemic heart disease remains the leading cardiovascular cause worldwide of loss of years of healthy life.

The natural history of atherosclerosis is strongly influenced by cumulative lifetime exposure to causal factors. For atherogenic lipoproteins in particular, the effect depends on both concentration and duration of exposure. All else being equal, a persistently high concentration of apoB-containing particles increases over time the probability of particle retention in the wall and thus plaque growth. This principle explains the extremely early onset of disease in familial hypercholesterolemia and, conversely, the substantial cardiovascular advantage associated with persistently low LDL exposure from the earliest stages of life.

The disease can now potentially be modified to a substantial degree. Intensive control of exposure to atherogenic lipoproteins, smoking, blood pressure, diabetes, and other cardiovascular determinants may slow or halt lesion progression, favorably modify plaque composition, and dramatically reduce the risk of atherothrombotic events. Revascularization, when indicated, instead corrects the hemodynamic consequences of specific lesions and does not eliminate the underlying atherosclerotic process, which continues to require permanent systemic therapy.

Etiology, risk factors, pathogenesis, and pathophysiology

Coronary atherosclerosis is multifactorial and has no single cause sufficient to produce it in every individual. It is nevertheless possible to distinguish exposures supported by particularly robust causal evidence from factors that modify probability, progression rate, or the propensity of plaque to become complicated. Among the best-demonstrated causal components is exposure of the arterial wall to apoB-containing lipoproteins, supported by concordant evidence from Mendelian genetics, prospective epidemiology, experimental studies, and randomized lipid-lowering trials.

LDL particles quantitatively represent the principal atherogenic particle population in most individuals. Plasma LDL cholesterol indicates the mass of cholesterol carried by LDL particles, whereas apoB approximates the total number of atherogenic particles because each atherogenic particle contains one apoB molecule. In diabetes, insulin resistance, hypertriglyceridemia, or other conditions in which cholesterol content per particle may vary, LDL-C and particle number may be discordant, and apoB may better describe the atherogenic lipoprotein burden.
The relationship between LDL and disease is cumulative. Genetic variants that cause persistently high LDL concentrations from birth produce a much greater increase in risk than a similar elevation beginning later in life, whereas variants that reduce lifetime LDL exposure provide particularly marked cardiovascular protection. This pattern is consistent with a process in which every period of exposure creates new opportunities for circulating particles to enter and remain within the arterial wall.

Familial hypercholesterolemia is the clearest clinical example. Pathogenic LDLR variants, less commonly APOB variants or gain-of-function PCSK9 variants, reduce LDL clearance or alter receptor interaction, causing markedly increased exposure from birth. In heterozygous forms, coronary atherosclerosis may present prematurely; in particularly severe homozygous or compound heterozygous forms, atherogenic burden may become extreme during childhood or adolescence. A substantial polygenic variability that contributes to population risk is added to the monogenic component.

Triglyceride-rich lipoproteins and especially their remnants also participate causally in atherogenesis. Triglyceride contained in the particles must not be interpreted as the sole atherogenic agent. Remnant particles derived from VLDL and chylomicrons contain cholesterol, can enter the intima when their size permits, and may be retained there, contributing to cholesterol deposition and inflammation. Hypertriglyceridemia is therefore largely an indicator of altered triglyceride-rich lipoprotein metabolism and an increased number or persistence of atherogenic remnants.

Lipoprotein(a) consists of an LDL-like particle containing apoB100 covalently bound to apolipoprotein(a). Its concentration is predominantly genetically determined by the LPA locus and varies enormously among individuals. Genetic, epidemiological, and mechanistic studies support a causal role in atherosclerosis. In addition to the cholesterol carried by the particle, Lp(a) transports oxidized phospholipids and has biological properties that may promote inflammation and atherothrombosis. Risk rises continuously with increasing concentration, whereas thresholds used in guidelines primarily serve practical stratification.

The principal initiating event in the arterial wall is subendothelial retention of apoB-containing particles. Lipoproteins cross the endothelium and may interact with proteoglycans in the intimal extracellular matrix. Binding between components of the lipoprotein surface and glycosaminoglycan chains slows their exit from the wall, increasing local particle residence. The response-to-retention theory identifies this retention as a fundamental step that precedes and fuels the atherosclerotic inflammatory response.
Lesion distribution is not random. Plaques tend to develop in regions where vascular geometry generates disturbed hemodynamic patterns, such as bifurcations and curved segments. Stable laminar flow and physiological shear stress favor an anti-inflammatory and antithrombotic endothelial phenotype associated, among other features, with expression of factors such as KLF2, nitric oxide production, and maintenance of barrier function. Oscillatory or disturbed flow instead favors an atheroprone endothelial phenotype.

Endothelial dysfunction includes reduced nitric oxide bioavailability, increased oxidative stress, altered permeability, expression of leukocyte adhesion molecules, and a shift in the balance among vasodilator, vasoconstrictor, antithrombotic, and prothrombotic mediators. It is not simply an end-stage consequence of plaque but participates in the earliest phases of disease and may persist even in segments where anatomical stenosis is modest.
Retained lipoproteins may undergo oxidative, enzymatic, and aggregative modifications. Modified lipids and other damage products activate endothelial and immune cells through pattern-recognition receptors and proinflammatory intracellular pathways. The endothelium increases adhesion-molecule expression, while chemokines such as CCL2 contribute to monocyte recruitment from the circulation. Atherogenesis therefore emerges from the interaction between retained extracellular lipids and a progressively self-sustaining local immune response.

Adherent monocytes cross the endothelium and mature within the intima into macrophages with heterogeneous functional states. These cells internalize modified lipoproteins through scavenger receptors, including CD36 and SR-A, whose activity is not regulated in the same manner as that of the physiological LDL receptor. Intracellular accumulation of cholesteryl esters produces classic foam cells. Phenotypically modified smooth muscle cells may also accumulate lipids and acquire foam-cell-like characteristics, so some foam cells in advanced human plaques do not originate from monocytes.

Intracellular cholesterol metabolism is an important regulatory point. Excess free cholesterol is cytotoxic and is esterified or transferred to efflux pathways involving, among others, ABCA1 and ABCG1. The efficiency of cholesterol efflux and reverse cholesterol transport may modulate cellular lipid content, but this does not mean that plasma HDL-C concentration alone is a causal therapeutic target equivalent to LDL. Intervention studies have shown that pharmacologically raising HDL-C does not in itself guarantee a reduction in cardiovascular events.

Cholesterol crystals, modified lipoproteins, and damage signals activate components of innate immunity. The NLRP3 inflammasome can promote maturation of interleukin-1β and interleukin-18, propagating the inflammatory response. IL-1β in turn stimulates downstream mediators, including IL-6, contributing to a hepatic acute-phase response detectable through biomarkers such as high-sensitivity C-reactive protein. Clinical demonstration that selective IL-1β inhibition can reduce cardiovascular events has provided direct evidence of the causal importance of inflammation in clinical atherosclerosis.
Adaptive immunity acts alongside innate immunity. T lymphocytes are present in human plaques and recognize antigens related to the atherosclerotic process. T helper 1 responses and interferon-γ may promote macrophage activation and interfere with matrix synthesis by smooth muscle cells, whereas regulatory populations may exert protective effects. The immune composition of plaque is highly dynamic and cannot be reduced to a simple dichotomy between “pro-” and “anti-atherogenic” cells.

Vascular smooth muscle cells have a central and ambivalent role. In the arterial media they maintain a predominantly contractile phenotype. During atherogenesis, signals derived from lipids, PDGF, cytokines, mechanical stress, and matrix induce phenotypic modulation, migration into the intima, and proliferation. Downregulation of the SRF-myocardin program and activation of programs regulated, among others, by KLF4 accompany the emergence of synthetic, inflammatory, osteogenic, or macrophage-like phenotypes.
Smooth muscle cell function is not exclusively pathogenic. Their ability to synthesize collagen and other extracellular-matrix components is essential for constructing the fibrous cap that separates the highly thrombogenic core from circulating blood. A plaque with a matrix-rich, relatively thick, and structurally intact cap may be clinically more stable than a less stenotic lesion characterized by a large necrotic core, intense inflammation, and a thin cap.

As the lesion progresses, cell death and failure to clear debris effectively increase. In early stages, efferocytosis allows phagocytes to remove apoptotic cells while preserving homeostasis. In advanced plaques, efferocytosis becomes ineffective; apoptotic cells undergo secondary necrosis, releasing lipids, membranes, and proinflammatory signals. The progressive confluence of extracellular debris generates the necrotic core characteristic of advanced fibroatheroma.
Expansion of the core and inflammation may weaken the cap. Macrophages and other cells produce metalloproteinases and proteases capable of degrading collagen and matrix, while inflammatory mediators may reduce collagen synthesis by smooth muscle cells. Rupture risk emerges from the interaction among tissue mechanical properties, cap thickness, core size, inflammatory infiltration, and the local distribution of stresses. No single parameter therefore inevitably determines rupture.

Neovascularization is another feature of advanced plaques. Microvessels arising mainly from the vasa vasorum may penetrate the lesion; their structural immaturity makes them permeable and susceptible to rupture. Intraplaque hemorrhage introduces erythrocytes, cholesterol-rich membranes, hemoglobin, heme, and iron into the tissue, contributing to core expansion, oxidative stress, and lesion progression.
Calcification is not simply passive calcium deposition. Smooth muscle cells may acquire an osteogenic phenotype and release extracellular vesicles that serve as mineralization nuclei. Inflammation, cell death, oxidative stress, and, in kidney disease, abnormalities of mineral metabolism promote this process. The mechanical consequences depend on calcification geometry: microscopic aggregates in areas under stress may locally increase force concentration, whereas dense, confluent calcification may accompany more chronic and fibrotic plaque stages.

Arterial hypertension accelerates atherogenesis through multiple mechanisms: increased mechanical stress on the wall, impaired endothelial function, oxidative stress, neurohormonal activation, and promotion of vascular remodeling. Its effect is not simply additive to dyslipidemia. An unfavorable hemodynamic environment may increase the susceptibility of specific arterial segments to lipid retention and subsequently influence stresses exerted on established plaques.
Tobacco smoking increases risk through exposure to numerous oxidizing and toxic compounds, reduced nitric oxide bioavailability, endothelial activation, inflammation, platelet and coagulation abnormalities, and changes in lipoprotein metabolism. Smoking therefore promotes both atheroma growth and the atherothrombotic transition that causes acute events. Cessation progressively reduces risk, although residual risk depends on accumulated atherosclerotic burden and the duration of previous exposure.

In diabetes mellitus, hyperglycemia, insulin resistance, atherogenic dyslipidemia, oxidative stress, advanced glycation end products, endothelial dysfunction, inflammatory activation, and a prothrombotic state all contribute. Diabetic dyslipidemia is frequently characterized by increased triglyceride-rich lipoproteins and remnants, reduced HDL-C, and relatively smaller, cholesterol-depleted LDL particles, a condition in which LDL-C may underestimate the number of apoB-containing particles.
Chronic kidney disease increases coronary risk through hypertension, lipoprotein abnormalities, persistent inflammation, oxidative stress, endothelial dysfunction, uremic toxins, and disturbances of calcium-phosphate metabolism that may accelerate vascular calcification. In advanced stages, the calcific component may be particularly substantial and coronary lesions may be diffuse and technically complex to treat.

Visceral adiposity and insulin resistance contribute through metabolic abnormalities, inflammation, and adipokine production. A specific role is played by coronary perivascular adipose tissue, which communicates bidirectionally with the arterial wall through paracrine signals. Vascular inflammation may modify the biology of surrounding fat and, conversely, dysfunctional adipose tissue may influence the endothelium and media. This interaction underlies the development of imaging biomarkers derived from pericoronary fat attenuation.

Age is one of the most powerful risk determinants because it integrates exposure duration, wall changes, immunosenescence, and accumulation of biological abnormalities. Among the latter, age-related clonal hematopoiesis has emerged. Somatic mutations in driver genes such as TET2, JAK2, and DNMT3A may expand hematopoietic clones. Some of these abnormalities, especially those with marked proinflammatory activity, are associated with greater atherosclerotic risk. Experimental models support a causal role for specific mutations, but systematic cardiovascular screening for clonal hematopoiesis and therapies directed specifically at this mechanism are not yet routine clinical practice.

Biological sex modifies age at onset, the risk-factor profile, and some disease characteristics but does not change the fundamental nature of atherogenic mechanisms. On average, women tend to develop clinical manifestations later than men, but risk increases substantially with age and in the presence of diabetes, smoking, hypertension, dyslipidemia, or inflammatory conditions. Underestimation of risk in women may contribute to diagnostic and therapeutic delays.
A family history of premature coronary disease may reflect rare genetic variants, polygenic burden, elevated Lp(a), familial aggregation of risk factors, and shared environmental components. Genetic risk is therefore not limited to familial hypercholesterolemia. Numerous common variants influence lipid metabolism, inflammation, thrombosis, blood pressure, and vascular biology, producing a continuum of genetic susceptibility in the population.

Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis, as well as HIV infection, are associated with increased cardiovascular risk through different combinations of inflammation, metabolic abnormalities, and, in some cases, treatment effects. These conditions may increase risk beyond that estimated from conventional factors alone. This does not, however, mean that atherosclerosis is an autoimmune disease in the classical sense: the process results from the interaction between atherogenic exposures and immune responses within the wall.
Physical inactivity, an unfavorable diet, obesity, inadequate sleep, and certain psychosocial determinants contribute to risk through effects on blood pressure, glucose and lipid metabolism, adiposity, endothelial function, and inflammation. Air pollution, particularly chronic exposure to fine particulate matter, is also recognized as a cardiovascular determinant through oxidative stress, systemic inflammation, and autonomic and vascular dysfunction. These factors act largely by modulating biological pathways that converge with those of traditional risk factors.

Conversely, some epidemiological associations historically considered potential causes have not translated into effective therapeutic targets. Pharmacologically raising HDL-C, lowering homocysteine with vitamins in unselected populations, or using antibiotics against hypothesized chronic infectious agents has not demonstrated sufficiently reliable prevention of atherosclerotic events to make these specific strategies for coronary disease. This distinction between epidemiological correlation and causality is essential when assessing risk factors.
As plaque progressively expands, the vessel may initially enlarge its external diameter through positive remodeling, preserving the lumen. When compensatory capacity is exceeded or remodeling becomes constrictive, luminal stenosis increases. This dynamic explains why a patient may have a high atherosclerotic volume before angiography shows severe stenosis and why plaque burden has prognostic significance independent of any single stenosis percentage.

The pathophysiological significance of a stenosis depends on its ability to limit increased flow when myocardial demand rises. At rest, autoregulatory mechanisms may preserve distal flow even in the presence of substantial narrowing; during exercise or stress, arteriolar vasodilation progressively reaches its limit and coronary reserve falls. The result is a mismatch between oxygen demand and supply that produces ischemia, metabolic changes, transient diastolic and systolic dysfunction, electrocardiographic changes, and, ultimately, symptoms.
The relationship between anatomical stenosis and ischemia is nevertheless imperfect. Lesion length, vessel diameter, diffuse disease, aortic pressure, microvascular resistance, and collateral circulation influence the pressure gradient and flow. A visually intermediate stenosis may therefore be physiologically relevant or irrelevant, whereas diffuse disease without extreme focal narrowing may cause a substantial pressure loss along the vessel. Invasive coronary physiology was developed specifically to measure this functional component.

The atherosclerotic endothelium loses part of its normal ability to modulate vascular tone, while microvascular dysfunction may coexist with epicardial disease. Fixed coronary narrowing therefore represents only one component of impaired perfusion. Dynamic vasoconstriction, microcirculatory abnormalities, and increased demand may contribute to symptom onset, explaining variability of the ischemic threshold within the same patient.
The most dangerous phase of disease occurs when the plaque surface loses its integrity and blood comes into contact with highly thrombogenic material or a denuded endothelial surface. Exposure of tissue factor, collagen, and other constituents induces platelet adhesion, activation, and aggregation and activates coagulation with thrombin and fibrin production. Thrombus size, the rate of endogenous fibrinolysis, vascular tone, and lesion geometry determine whether the event remains silent, causes stenosis progression, or produces an acute coronary syndrome.

Pathological anatomy, progression, and coronary plaque phenotypes

The normal coronary wall consists of intima, media, and adventitia. Atherosclerosis primarily affects the intima but, as it progresses, profoundly modifies the entire vascular architecture, affecting the media, external elastic lamina, vasa vasorum, adventitia, and perivascular adipose tissue. Coronary atheroma is generally eccentric, and a vessel cross-section may simultaneously contain regions with different tissue compositions.
Early changes may appear long before clinical manifestations. Collections of intimal foam cells form so-called fatty streaks, which must not automatically be regarded as inevitable precursors of clinically relevant plaques. Progression to advanced lesions requires persistent atherogenic exposure, lipid retention, and development of more complex structural changes.

An important step is extracellular lipid accumulation within a proteoglycan-rich thickened intima, termed pathological intimal thickening in contemporary pathology. Confluence of lipid deposits, cell death, and expansion of debris subsequently leads to necrotic-core formation and progression to fibroatheroma.
A fibroatheroma contains a lipid-necrotic core covered by a cap composed mainly of collagen, smooth muscle cells, and extracellular matrix. The relative amounts of these components vary enormously. A thick, collagen-rich cap tends to provide greater mechanical resistance, whereas a thin cap with substantial macrophage infiltration and a reduced smooth muscle component has features associated with rupture.

The thin-cap fibroatheroma, or TCFA, is the classic histological lesion considered a precursor of rupture. In the traditional pathological definition, it has a large necrotic core covered by a macrophage-infiltrated fibrous cap less than 65 µm thick, without superimposed luminal thrombus. This threshold derives from histopathological studies and must not be interpreted as an absolute biological boundary.
Plaques responsible for events are not uniformly distributed along the coronary tree. High-risk lesions and ruptures are frequently located in the proximal and mid segments of the major epicardial arteries, regions in which geometry, bifurcations, and shear stress patterns may promote atherogenesis and destabilization. Location is also clinically important because proximal thrombosis may compromise a larger amount of myocardium.

During early growth, an increase in plaque volume may be accompanied by expansion of the external elastic membrane; this expansive remodeling makes it possible to accommodate a considerable amount of atherosclerotic tissue without a proportional reduction in lumen size. Consequently, an apparently minimally altered coronary angiogram does not necessarily exclude significant disease of the vessel wall.
Remodeling may subsequently become insufficient or acquire constrictive characteristics, resulting in progressive narrowing. Chronic fibrotic lesions may have a markedly reduced lumen, whereas other biologically active plaques remain relatively nonstenotic. Stenotic severity and risk of thrombosis are therefore only partially correlated properties.

Calcification extends across a spectrum from microscopic deposits to large confluent plaques. Microcalcifications located within a thin cap may create heterogeneity in elastic properties and locally concentrate mechanical stress. Dense macrocalcification frequently reflects more chronic disease and may accompany healing and stabilization processes, while also representing an indicator of a high overall atherosclerotic burden.
This distinction explains an apparently paradoxical phenomenon observed during effective lipid-lowering therapies: clinical risk may decrease while some plaques become more densely calcified. An increase in calcium density therefore does not necessarily indicate dangerous biological progression. By contrast, the total coronary artery calcium score retains strong prognostic significance because it reflects the cumulative amount of calcified atherosclerosis developed by the patient.

Plaque rupture occurs when a discontinuity extends through the fibrous cap and brings the blood into contact with the necrotic core. Lipid material, tissue factor, and exposed matrix rapidly induce thrombus formation. The thrombus may be nonocclusive, intermittent, or completely occlusive, and its extent, more than the morphology of the plaque considered in isolation, determines the immediate clinical presentation.
Rupture tends to occur in regions with a thinned and inflamed cap, often at the plaque shoulders, where geometry and mechanical discontinuities may increase stress. Macrophages, matrix degradation, and reduced collagen synthesis contribute to tissue fragility. Rupture is not, however, the inevitable outcome of every TCFA: many high-risk lesions remain silent, evolve, partially regress, or heal.

Superficial erosion is a distinct mechanism. Histologically, it is characterized by the presence of thrombus over a plaque with an intact fibrous cap but lacking the normal endothelial lining in the affected area. The underlying lesion tends to be relatively rich in smooth muscle cells and proteoglycans and may have a less prominent lipid core than classic ruptured plaques.
The pathogenesis of erosion includes interactions among disturbed flow, endothelial injury or desquamation, a hyaluronic acid-rich matrix, activation of pattern-recognition receptors, neutrophils, and formation of neutrophil extracellular traps. The denuded surface promotes platelet adhesion and formation of a frequently platelet-rich thrombus. Erosion now accounts for approximately one third of acute coronary syndromes in contemporary series, with variability among populations and methods used.

In vivo, OCT does not reliably visualize the endothelial layer directly; the intracoronary diagnosis of erosion is therefore inferential and is based primarily on the presence of thrombus over a plaque with a fibrous cap intact and no evidence of rupture. The "plaque erosion" identified by OCT must therefore be distinguished from the strict histological definition obtainable from pathological examination.
Another phenotype recently redefined with greater precision is plaque fissure. A fissure is a lateral tear that extends through the relatively thick fibrous cap of an eccentric lesion and terminates in a small necrotic core. It is associated with intraplaque thrombosis and generally with little or no luminal thrombosis, distinguishing it from classic rupture, which produces broader communication between blood and the necrotic core.

The eruptive calcified nodule is a less common substrate for coronary thrombosis. It is characterized by fragments of dense calcium protruding into the lumen, disrupting the cap and endothelial lining and being associated with fibrin deposition and thrombus. It is important to distinguish it from simple nodular calcification covered by an intact cap and endothelium, which is not itself a thrombotic lesion.
Calcified nodules are particularly clinically relevant in heavily calcified segments subjected to repeated mechanical deformation. Advanced age, chronic kidney disease, and diabetes are frequently associated with a greater coronary calcium burden. Nodular lesions may also represent a technical challenge during percutaneous interventions because of calcium rigidity, difficulty in expanding the stent, and the possibility of calcific protrusion.

Nonocclusive thrombotic events may go unnoticed. A thrombus formed over a rupture or erosion may be progressively organized, incorporated into the wall, and replaced by matrix. Repeated episodes of plaque healing produce successive layers of fibrous tissue and may result in a gradual, stepwise increase in lesion volume without any recognized clinical episode.
The presence of layers within the plaque, documented histologically and by intracoronary imaging, attests to this history of injury and repair. The healing process is protective because it prevents persistent thrombogenic exposure, but it may simultaneously contribute to stenosis growth. Advanced atherosclerosis must therefore be regarded as a dynamic balance among lipid deposition, inflammation, surface injury, thrombosis, and repair.

Intraplaque hemorrhage may produce rapid expansion of atheroma volume even in the absence of luminal thrombosis. Erythrocytes introduced into the lesion contribute cholesterol-rich membranes, while heme and iron may amplify oxidative stress and inflammation. The presence of intraplaque hemorrhage is therefore associated with features of progression and instability.
Neovascularization provides the structural substrate for many intraplaque hemorrhages. Plaque microvessels are fragile, lack normal structural maturity, and are permeable to cells and plasma proteins. The increased inflammatory burden and metabolic demand of the plaque may further promote angiogenesis, creating a cycle in which growth, tissue hypoxia, neovessels, and hemorrhage sustain one another.

Inflammatory tissue is not uniformly distributed. Macrophages and lymphocytes may concentrate in the cap and shoulders of the lesion, while other regions become predominantly fibrotic or calcified; for this reason, the same plaque may simultaneously contain lipid, fibrous, and calcific tissue with different biological and mechanical properties.
Contemporary assessment of high-risk plaque therefore considers numerous attributes: large plaque burden, lipid-necrotic core, thin cap, macrophage inflammation, endothelial injury, positive remodeling, intraplaque hemorrhage, neovascularization, cholesterol crystals, microcalcifications, superficial calcified nodules, and adverse local hemodynamic conditions; these features probabilistically increase risk but do not allow the fate of an individual lesion to be predicted with certainty.

The most recent scientific position emphasizes that the term "vulnerable plaque," traditionally almost synonymous with a TCFA susceptible to rupture, is too narrow. Acute coronary syndromes may result from rupture, erosion, or a calcified nodule, which have different precursors. Risk assessment must therefore encompass all the principal pathways leading to thrombosis and integrate them with patient-specific factors.
The risk of an event attributable to a single high-risk plaque is also lower than initially suggested by early conceptual models. Many prospectively identified lesions do not cause events during follow-up, whereas risk increases in the presence of a high overall atherosclerotic burden; this shifts therapeutic attention away from searching for a single lesion "destined" to rupture and toward systemic treatment of the entire patient with atherosclerosis.

Coronary plaques in the same individual may simultaneously be at different stages. A coronary artery may contain stable fibrotic lesions, TCFAs, calcified segments, healed plaques, and areas with minimal disease. The multifocal and temporally dynamic nature of the disease explains why revascularization of one stenosis does not protect against future complications of other plaques and why systemic treatment of causal factors remains essential even after a technically perfect PCI or bypass operation.
Intensive lipid-lowering therapy can modify this landscape. Marked reduction in atherogenic lipoproteins decreases the influx of new cholesterol into the wall, progressively reduces the lipid and inflammatory components, may promote a relative increase in the fibrous component, and, in some imaging studies, results in modest volumetric plaque regression. The clinical benefit therefore derives not only from a reduction in stenosis, which may be minimal, but primarily from modification of the biology of the entire coronary tree.

Calcification observed during treatment must be interpreted in the same context. Greater calcium density may accompany the transformation of a lipid-rich, inflammatory lesion into a more fibrotic and mineralized structure; for this reason, progression of the calcium score is not a reliable method for judging failure of statin therapy in an individual patient, and serial CAC testing must not be used as a surrogate for biological assessment of the therapeutic response.
Finally, the interaction among the wall, blood, and underlying myocardium determines the clinical relevance of each lesion. A small thrombus may remain clinically silent if it is rapidly lysed; thrombosis in the same type of plaque may cause an extensive infarction if it occludes a large proximal branch; a severe stenosis may produce ischemia without thrombosis; a mildly stenotic plaque may suddenly cause a fatal event; this heterogeneity is the pathological basis of the wide clinical variability of coronary atherosclerosis.

Clinical manifestations

For much of its natural history, coronary atherosclerosis is asymptomatic. The presence of a plaque does not itself cause pain, and arterial remodeling may maintain an adequate lumen for many years. The disease is therefore frequently discovered incidentally through coronary calcifications visible on a CT scan performed for other reasons, by calcium scoring, or through CCTA performed as part of the diagnostic stratification of symptoms not yet definitively attributed to the heart.
When the patient becomes symptomatic, the medical history must begin with precise characterization of the complaint. Contemporary guidelines favor a direct description of symptoms over the traditional rigid classification into "typical" or "atypical" pain. Site, quality, duration, precipitating factors, threshold of onset, mode of resolution, radiation, associated symptoms, course over time, and relationship to physical activity, emotional stress, cold exposure, and meals must be identified.

The classic chronic manifestation is retrosternal chest discomfort described as pressure, heaviness, tightness, or constriction, provoked relatively reproducibly by increased myocardial demand and relieved by rest or sublingual nitrate. It may radiate to one or both arms, the shoulders, neck, jaw, back, or epigastrium. It usually lasts minutes; extremely brief, stabbing, instantaneous pain or continuous pain unchanged for many hours is less likely to be due to myocardial ischemia, although these features alone cannot exclude it.
The ischemic threshold depends on the relationship between demand and the capacity to increase coronary blood flow. Physical exertion, tachycardia, increased blood pressure, cold, and adrenergic stress increase oxygen consumption and may trigger symptoms. In hemodynamically significant stenoses, resting flow may remain adequate, whereas the increase required during exercise can no longer be achieved.

Exertional dyspnea may represent an anginal equivalent. Transient ischemia may increase left ventricular filling pressures through diastolic dysfunction and, when more extensive, reduced systolic function. The patient may therefore primarily experience dyspnea, reduced exercise tolerance, fatigue, or a sensation of weakness rather than chest pain.
Less classic presentations are particularly important in older adults, patients with diabetes, women, and individuals with comorbidities that modify symptom perception or expression. Nausea, sweating, dyspnea, fatigue, epigastric pain, or jaw discomfort may accompany or replace chest pain. None of these presentations is specific, however, and diagnosis must derive from integration of the clinical picture and diagnostic tests.

The temporal stability of symptoms is fundamental. A relatively reproducible exertional pattern that remains unchanged over time suggests a chronic coronary syndrome, whereas new pain at rest, a marked increase in the frequency or intensity of episodes, a lower threshold for onset, or prolonged pain should raise suspicion of an acute coronary syndrome and requires immediate assessment with ECG and high-sensitivity cardiac troponin.
Acute thrombosis over a plaque may cause a spectrum ranging from transient ischemia without necrosis to myocardial infarction with or without persistent ST-segment elevation. STEMI, NSTEMI, and unstable angina describe the clinical-electrocardiographic presentation and the presence or absence of necrosis, not the morphological mechanism of the plaque. Rupture and erosion may both produce different clinical phenotypes depending on the extent, persistence, and location of thrombosis.

In acute infarction, pain is frequently more intense and prolonged than in chronic angina and may occur at rest. Sweating, nausea, vomiting, dyspnea, agitation, a sense of impending death, or syncope may be associated. The absence of pain does not exclude infarction, particularly in older adults, patients with diabetes, or severely ill patients.
Some infarctions are silent or paucisymptomatic and are recognized later because of electrocardiographic abnormalities, regional wall-motion abnormalities, a scar documented by magnetic resonance imaging, or functional consequences. Diabetic autonomic neuropathy may reduce the perception of ischemic pain, but silent ischemia is also possible in individuals without diabetes.

Sudden cardiac death may be the first manifestation of the disease. Acute ischemia and infarction may create marked electrical instability and cause ventricular tachycardia or ventricular fibrillation. In other patients, sudden death results from scars of previous infarctions that form the anatomical substrate for ventricular reentry circuits.
A progressively severe stenosis may lead to chronic ischemia and the development of collateral circulation. Collaterals may mitigate the severity of ischemia and alter symptoms but do not indicate normalization of perfusion or eliminate the risk associated with diffuse disease. A chronic total occlusion may be surprisingly paucisymptomatic when collateral circulation is well developed, or it may cause disabling angina and extensive ischemia.

Myocardial loss resulting from repeated or extensive infarctions may evolve into ischemic cardiomyopathy. At this stage, the patient may primarily have dyspnea, orthopnea, reduced exercise tolerance, edema, asthenia, or recurrent hospitalizations for heart failure, while angina may be absent. A history of previous coronary syndromes, revascularizations, or risk factors may point toward an ischemic etiology.
During history taking, determinants of disease probability and prognosis must be systematically investigated: age, current or previous smoking, hypertension, diabetes, dyslipidemia, kidney disease, obesity, physical activity, previous cardiovascular events, peripheral artery disease, cerebrovascular events, chronic inflammatory diseases, and a family history of premature coronary artery disease.

Current therapy provides essential information. Lipid-lowering treatment and adherence, antiplatelet or anticoagulant agents, antihypertensive drugs, antianginal agents, and medications for diabetes and heart failure must be documented. The occurrence of symptoms despite apparently adequate treatment requires differentiation among disease progression, poor adherence, failure to achieve targets, nonepicardial ischemic mechanisms, and alternative diagnoses.
A personal or family history of markedly elevated LDL, very early coronary events, or tendon xanthomas should raise suspicion of familial hypercholesterolemia. Elevated Lp(a) may explain some residual risk or strong familial clustering even when LDL-C is not exceptionally high.

The physical examination may be completely normal in a patient with coronary atherosclerosis, even when advanced. No specific physical sign can confirm or exclude the presence of plaque. Rather, the examination serves to identify hemodynamic instability, cardiac consequences of the disease, concomitant disorders, signs of atherosclerosis in other vascular territories, and manifestations of predisposing conditions.
Assessment begins with general appearance and vital signs: heart rate, blood pressure, oxygen saturation when indicated, and signs of hypoperfusion or respiratory distress. Hypotension, persistent tachycardia, altered mental status, cold skin, oliguria, or hypoxemia in the context of an ischemic syndrome may indicate hemodynamic compromise and require urgent management.

Cardiac examination looks for a third or fourth heart sound, new murmurs, changes in heart sound intensity, and signs of congestion. A new systolic murmur after infarction may signal ischemic mitral regurgitation or a mechanical complication. Pulmonary crackles, elevated jugular venous pressure, edema, and other signs of congestion instead document the hemodynamic consequences of heart failure.
Palpation of peripheral pulses and examination for signs of peripheral artery disease allow recognition of a polyvascular phenotype, which is associated with particularly high risk. Vascular bruits may suggest disease in other territories, but their absence does not exclude systemic atherosclerosis.

Tendon xanthomas, particularly involving the Achilles tendon and the extensor tendons of the hands, are an important finding when familial hypercholesterolemia is suspected. Xanthelasmas and corneal arcus have much lower specificity, especially with advancing age, but a very early corneal arcus may contribute to clinical suspicion in the appropriate context.
In a patient with acute chest pain, the examination must simultaneously look for potentially fatal alternative diagnoses. Differences in pulse or blood pressure, neurological deficits, or a murmur of aortic regurgitation may point toward aortic dissection; tachycardia, hypoxia, and signs of venous thrombosis may suggest pulmonary embolism; a pericardial friction rub and positional pain point toward pericarditis. Coronary assessment must therefore not occur in isolation from the emergency context.

The relationship between symptoms and anatomy may be complex. Patients with nonobstructive plaques may have angina because of endothelial dysfunction, vasospasm, or microvascular dysfunction, whereas some patients with severe stenoses are paucisymptomatic because of reduced activity, neuropathy, gradual adaptation, or collateral circulation. Pain intensity is therefore not a reliable measure of atherosclerotic burden.
The onset of symptoms after previous revascularization requires a new analysis of the entire coronary system. Possibilities include progression of native plaques, restenosis, stent thrombosis, graft degeneration, ischemia due to diffuse disease, microvascular dysfunction, and noncardiac causes. Previous PCI therefore does not make a new atherosclerotic manifestation unlikely.

Finally, clinical assessment must establish not only whether symptoms may be ischemic, but also their functional severity. The frequency of episodes, the activity required to provoke them, limitation of normal activities, response to therapy, and impact on quality of life are fundamental in deciding the intensity of antianginal therapy and the appropriateness of further investigations or revascularization.

Investigations and diagnosis

Coronary atherosclerosis in the pathological sense does not have a single set of official international diagnostic criteria analogous to those available for some other diseases. Diagnosis derives from anatomical demonstration of coronary plaque or demonstration of atherosclerotic coronary artery disease in the appropriate clinical context. Three questions must also be kept distinct: the presence of atherosclerosis, the presence of an obstructive stenosis, and the presence of ischemia caused by the lesion.
According to the 2024 ESC guidelines on chronic coronary syndromes, assessment of a symptomatic patient follows a stepwise sequence. First, symptoms, general health, risk factors, and any features of instability are defined; ECG, appropriate blood tests, and echocardiography when indicated are then performed; the clinical likelihood of obstructive coronary artery disease is subsequently estimated and the most appropriate anatomical or functional test is selected.

Any suspicion of an acute coronary syndrome interrupts the elective algorithm. Recent or persistent pain at rest, hemodynamic instability, ischemic ECG changes, or other warning features require an urgent pathway based on a 12-lead ECG, high-sensitivity cardiac troponin, and risk stratification, with rapid access to invasive coronary angiography when indicated.
In chronic assessment, the resting ECG may be normal even in the presence of significant coronary artery disease. Q waves may suggest a previous infarction; ST-segment or T-wave abnormalities may reflect ischemia or other conditions; conduction disturbances, hypertrophy, and arrhythmias modify the overall assessment and may influence the choice of the next test. No resting electrocardiographic abnormality is specific to atherosclerotic plaque.

Initial blood tests have different diagnostic and prognostic purposes. A lipid profile, blood glucose and HbA1c, complete blood count, creatinine with estimated kidney function, and other selected tests make it possible to characterize risk factors and comorbidities. Anemia, thyroid dysfunction, or other conditions may also aggravate ischemic symptoms by altering oxygen demand or delivery.
The lipid profile should include at least total cholesterol, HDL-C, triglycerides, and estimated or measured LDL-C. Non-HDL-C represents the total amount of cholesterol contained in atherogenic particles and is particularly useful when triglycerides are elevated. ApoB may add information when discordance between LDL-C and particle number is suspected, especially in diabetes, hypertriglyceridemia, and when very low LDL-C values have been achieved.

The 2026 US guidelines recommend measuring Lp(a) at least once in adulthood for risk assessment. A concentration of at least 125 nmol/L or 50 mg/dL is used as a level of increased risk, while recognizing that the relationship with risk is continuous and that conversion between molar and mass units cannot be performed with a single universal factor because of variability in apo(a) isoforms.
High-sensitivity C-reactive protein may contribute to characterization of residual inflammatory risk, but it does not diagnose coronary atherosclerosis. Similarly, no circulating inflammatory biomarker can identify an unstable coronary plaque in an individual patient with sufficient specificity.

Cardiac troponin is a biomarker of myocardial injury, not of atherosclerosis. A dynamic rise and/or fall in cardiac troponin with at least one value above the sex-specific 99th percentile, associated with one or more clinical, electrocardiographic, or imaging findings of acute myocardial ischemia, allows a diagnosis of myocardial infarction to be made in the appropriate context according to the universal definition. A normal troponin does not exclude the presence of even extensive coronary atherosclerosis.
Transthoracic echocardiography assesses global and regional ventricular function, valves, and alternative diagnoses. A regional reduction in contractility may indicate ischemia or previous infarction, but it does not necessarily identify the responsible plaque precisely. Left ventricular ejection fraction also has important prognostic significance in known coronary artery disease.

In a patient with symptoms compatible with chronic coronary syndrome, the 2024 ESC guidelines recommend estimating the risk factor-weighted clinical likelihood of obstructive epicardial coronary artery disease by integrating age, sex, symptom characteristics, and major risk factors. The model must be further adjusted in the presence of clinical, electrocardiographic, echocardiographic, or imaging findings that substantially modify the probability.
A very low probability of 5% or less generally allows deferral of further testing to be considered if there are no other clinical reasons. In the low range above 5% and up to 15%, the usefulness of testing should be individualized, and the calcium score may assist reclassification. A probability above 15% and up to 50% is moderate, above 50% and up to 85% is high, and above 85% is very high; across these ranges, the indication for functional imaging or invasive coronary angiography progressively increases according to the context.

The coronary artery calcium score obtained by noncontrast CT quantifies coronary calcification, generally using the Agatston score. The presence of coronary calcium is evidence of calcified coronary atherosclerosis, and calcium burden has strong prognostic value. The test is particularly useful for preventive risk stratification in selected individuals for whom the therapeutic decision remains uncertain.
A CAC of zero identifies a population at generally low risk, but it does not demonstrate the absolute absence of atherosclerosis. Noncalcified plaques may be present, especially in younger individuals, symptomatic patients, or certain high-risk conditions. CAC must therefore not be used as the sole method for excluding coronary artery disease in a patient with significant clinical suspicion.

CCTA is the principal noninvasive method for directly documenting coronary plaque and lumen anatomy. It can identify calcified, noncalcified, and mixed lesions, estimate stenosis severity, assess disease distribution and burden, and identify high-risk anatomy. In the 2024 ESC guidelines, it is particularly indicated as an initial test in patients with a low-to-moderate likelihood of obstructive coronary artery disease.
The principal conceptual advantage of CCTA over luminography is visualization of the coronary wall. A nonobstructive plaque thus acquires diagnostic and prognostic relevance, allowing recognition of disease that might be underestimated by tests focused exclusively on ischemia or by coronary angiography in the presence of positive remodeling.

CCTA features associated with high-risk plaques include low attenuation, positive remodeling, spotty calcifications, and the napkin-ring sign; these findings increase the statistical risk of events and may contribute to stratification, but they are not pathognomonic and do not identify with certainty which plaque will cause a future acute coronary syndrome.
The percentage of anatomical stenosis must not automatically be equated with hemodynamic significance. In particular, for intermediate stenoses, CCTA may be supplemented by functional imaging or, in selected settings, computational methods for estimating coronary physiology. The choice depends on examination quality, clinical probability, local availability, and the potential need to proceed to invasive coronary angiography.

Functional imaging includes stress echocardiography, single-photon emission computed tomography, PET, and stress cardiac magnetic resonance imaging; these methods do not directly diagnose plaque but establish whether the disease impairs myocardial perfusion or function. The distribution and extent of ischemia provide important prognostic information and may guide revascularization.
PET has the advantage of being able to quantify absolute myocardial blood flow and flow reserve, providing information on diffuse epicardial disease and microvascular function. Magnetic resonance imaging simultaneously allows assessment of perfusion, ventricular function, and tissue characterization, including identification of myocardial scar by late gadolinium enhancement.

Exercise electrocardiographic testing remains useful in some settings but has lower diagnostic accuracy than modern imaging methods and does not identify plaque. In contemporary guidelines, anatomical or functional imaging is generally preferred when available and appropriate, especially when the objective is to define anatomy, ischemia, and risk precisely.
Invasive coronary angiography is indicated when the probability of obstructive disease is very high, when severe or refractory symptoms, high-risk noninvasive findings, or an acute coronary syndrome are present, or when anatomical knowledge is expected to lead directly to revascularization. It provides excellent temporal and spatial resolution of the lumen but, without intracoronary imaging, provides limited information on wall composition.

Intermediate angiographic stenoses should be assessed physiologically when their significance has not already been clarified by noninvasive evidence. Fractional flow reserve measures the distal pressure ratio during maximal hyperemia, and a value ≤0.80 conventionally identifies a hemodynamically significant lesion. iFR and other nonhyperemic indices allow a similar assessment without pharmacological induction of hyperemia; for iFR, the conventional threshold used in studies and practice is ≤0.89.
Intracoronary physiology answers the question of whether a stenosis significantly reduces flow, but it does not describe plaque composition. An FFR-negative lesion may contain a large amount of atheroma and retain long-term prognostic significance; conversely, the decision to revascularize a stable stenosis must be based primarily on its hemodynamic impact, symptoms, and anatomical context, not solely on the visual percentage.

IVUS uses intravascular ultrasound and makes it possible to measure vessel dimensions, lumen area, plaque burden, remodeling, and calcium distribution, with greater tissue penetration than OCT. It is particularly useful in planning and optimizing PCI, in left main lesions, and in complex anatomy, and it has also provided much of the knowledge on volumetric progression and regression of atheroma.
OCT uses near-infrared light and has markedly higher resolution than IVUS, allowing detailed assessment of the fibrous cap, thrombus, surface discontinuities, and calcific structures. Its lower penetration depth, however, limits its ability to measure the entire volume of large plaques. It is the most suitable invasive method for distinguishing in vivo between rupture and a plaque with an apparently intact cap in the setting of an acute coronary syndrome.

Other intracoronary methods, such as near-infrared spectroscopy integrated with IVUS, can identify lipid-rich tissue and quantify lipid core burden; these tools have substantial research value and may provide additional information in selected settings, but characterization of a high-risk plaque does not automatically constitute an indication for focal preventive treatment.
Analysis of pericoronary adipose tissue by CCTA may provide indirect biomarkers of coronary inflammation. The fat attenuation index and related methods exploit changes in the adipocyte phenotype induced by inflammatory signals originating from the wall; these tools are promising for risk stratification and precision medicine, but they do not constitute an independent diagnostic criterion required to recognize atherosclerosis in routine practice.

Molecular plaque imaging also remains predominantly specialized or experimental. PET with different tracers and, in particular, the use of 18F-sodium fluoride to identify microcalcification activity have enabled important studies of lesion biology, but they are not part of the standard diagnostic pathway for most patients with suspected coronary artery disease.
Once atherosclerosis has been documented, its prognostic profile must be defined: number of vessels involved, presence of left main or proximal disease, overall plaque burden, severity and physiological significance of stenoses, left ventricular function, extent of ischemia, previous infarctions, diabetes, kidney function, bleeding risk, and the presence of atherosclerotic disease in other vascular territories.

The differential diagnosis must include cardiovascular and noncardiovascular causes of symptoms. Major cardiac conditions include epicardial vasospasm, microvascular angina, spontaneous coronary artery dissection, coronary embolism, coronary anomalies, myocarditis, pericarditis, cardiomyopathies, and valvular heart disease. Extracoronary emergencies include aortic dissection and pulmonary embolism; gastrointestinal, musculoskeletal, and pulmonary causes are other common diagnoses.
When CCTA or coronary angiography excludes obstructive epicardial stenoses but symptoms compatible with ischemia persist, assessment must not automatically stop. The ESC guidelines recognize the ANOCA/INOCA spectrum and recommend considering microvascular dysfunction and vasospasm using noninvasive or invasive functional testing in appropriate patients. These mechanisms may coexist with nonobstructive atherosclerosis.

The diagnosis of familial hypercholesterolemia should be considered in patients with very high LDL, premature disease, or a suggestive family history. In such cases, assessment may include validated clinical criteria, genetic testing when appropriate, and cascade screening of family members; this is not a criterion for diagnosing coronary atherosclerosis, but it makes it possible to recognize one of its most important causal conditions.
Finally, serial changes in CAC should not be used as a direct surrogate for the biological response to therapy. Statins may increase calcium density while reducing events. Follow-up should therefore focus on control of causal factors, achievement of therapeutic targets, symptoms, ventricular function, and new clinical findings, reserving repeat imaging for questions capable of materially changing management.

Treatment and prognosis

Treatment of coronary atherosclerosis has two distinct but complementary objectives: modifying the natural history of the disease by reducing progression and atherothrombosis, and controlling the hemodynamic consequences of lesions already present. The first objective requires lifelong systemic therapy; the second includes antianginal drugs and, in appropriate patients, revascularization by PCI or coronary artery bypass grafting.
At every stage, management must begin with smoking cessation, a heart-healthy diet, appropriate physical activity, and control of adiposity, blood pressure, glucose metabolism, and atherogenic lipoproteins; these interventions must not be regarded as ancillary to pharmacotherapy: they act simultaneously on multiple causal mechanisms and reduce the risk of cardiovascular events and other chronic diseases.

Smoking cessation is one of the measures with the greatest prognostic impact. Nicotine dependence, secondhand exposure, and relapse risk must be addressed through counseling and, when indicated, evidence-based pharmacological treatment. Simply reducing the number of cigarettes does not provide the same protection as complete abstinence.
The dietary pattern should prioritize vegetables, fruit, legumes, whole grains, nuts, fish, and sources of unsaturated fats, while limiting trans fats, excess saturated fat, processed meats, ultra-processed foods, added sugars, and excess sodium. A Mediterranean-style diet is among the dietary patterns with the strongest support for cardiovascular prevention. Replacing saturated fats with unsaturated fats is metabolically different from replacing them with refined carbohydrates.

Regular aerobic physical activity improves functional capacity, blood pressure, insulin sensitivity, weight control, and prognosis. In clinically stable patients, at least 150-300 minutes per week of moderate aerobic activity or 75-150 minutes of vigorous activity are generally recommended, with resistance exercises on designated days and with intensity and prescription tailored to the clinical situation. After a coronary syndrome or revascularization, structured cardiac rehabilitation provides prognostic and functional benefits.
Reduction of atherogenic lipoproteins is the principal treatment directed specifically at the biological substrate of the disease. In Europe, a patient with clinically documented atherosclerotic coronary disease generally belongs to the very-high cardiovascular risk category, and the ESC/EAS target remains a reduction in LDL-C of at least 50% from baseline and an LDL-C below 55 mg/dL, corresponding to 1.4 mmol/L.

The 2026 ACC/AHA guidelines converge on a target below 55 mg/dL and non-HDL-C below 85 mg/dL in patients with ASCVD at very high risk. In patients with clinical ASCVD not classified as being at very high risk, they indicate at least a ≥50% reduction in LDL-C and a target below 70 mg/dL, recognizing further intensification toward values below 55 mg/dL as reasonable in selected patients. The differences reflect different classification systems more than a different interpretation of LDL causality.
First-line therapy is a high-intensity statin at the maximum tolerated dose, typically atorvastatin 40-80 mg or rosuvastatin 20-40 mg when appropriate. Inhibition of HMG-CoA reductase reduces hepatic cholesterol, increases LDL receptor expression, and accelerates removal of apoB-containing particles from plasma. The reduction in events is primarily proportional to the absolute and sustained reduction in LDL exposure.

Statins also modify plaque composition, reducing lipid content and inflammatory activity and promoting more stable structural features. The expression "plaque stabilization" therefore describes a set of biological transformations broader than a simple change in the percentage of stenosis. Clinical benefit may be substantial even when luminal diameter changes little.
When the maximally tolerated statin does not achieve the target, ezetimibe is one of the principal add-on therapies. By inhibiting NPC1L1 in the intestine, it reduces cholesterol absorption and produces further upregulation of LDL receptors. The cardiovascular benefit of adding it to a statin has been demonstrated after acute coronary syndrome, confirming that further LDL reduction achieved through a nonstatin mechanism produces a further reduction in events.

The monoclonal antibodies against PCSK9, evolocumab and alirocumab, prevent LDL receptor degradation and can produce very large reductions in LDL-C. Randomized trials have demonstrated a reduction in cardiovascular events in patients with ASCVD already receiving optimized lipid-lowering therapy. More recent data with evolocumab have also extended the evidence of benefit to high-risk populations with atherosclerosis or diabetes but no previous infarction or stroke.
Bempedoic acid inhibits ATP-citrate lyase upstream of HMG-CoA reductase and is activated predominantly in the liver. It lowers LDL-C and has demonstrated a reduction in cardiovascular events in patients who are intolerant of statins or unable to take recommended doses. It may be used alone or with ezetimibe and is particularly useful when further reductions in LDL-C are needed and a high-intensity statin is not feasible.

Inclisiran is a small interfering RNA directed against hepatic PCSK9 synthesis and produces a sustained reduction in LDL-C with widely spaced dosing. The 2026 guidelines recognize its lipid-lowering efficacy in selected settings; at the time of this review, however, trials dedicated to hard cardiovascular outcomes have not yet provided the same level of evidence available for anti-PCSK9 monoclonal antibodies. When the priority is a therapy with a benefit on events that has already been directly demonstrated, this difference in evidence must be considered.
The choice among drugs need not necessarily follow a long sequence of failures. In a patient far from target, especially after an acute coronary syndrome, statin monotherapy can be expected to be insufficient. The most recent recommendations therefore encourage earlier use of combination therapy, including the combination of a high-intensity statin and ezetimibe during hospitalization for ACS when achieving the target with monotherapy appears unlikely.

In patients with subclinical atherosclerosis, calcific burden may modify treatment intensity. The 2026 ACC/AHA guidelines propose progressively more aggressive targets as CAC increases: a CAC of 1 to 99 and below the 75th percentile generally points toward a moderate-intensity statin and LDL-C below 100 mg/dL; a CAC of 100 to 299 or at least the 75th percentile points toward LDL-C below 70 mg/dL; values of 300 to 999 require at least a 50% reduction and LDL-C below 70 mg/dL, with further intensification toward LDL-C below 55 mg/dL being reasonable, whereas a CAC ≥1000 identifies a very high burden for which pursuing a ≥50% reduction and LDL-C below 55 mg/dL is recommended.
Elevated Lp(a) requires particularly aggressive control of all modifiable factors. Its level is minimally affected by lifestyle, and statins do not reduce it, although they remain fundamental for lowering LDL-C and overall risk. Anti-PCSK9 antibodies produce a moderate reduction in Lp(a) as well as LDL-C. Lipoprotein apheresis may be used in highly selected situations depending on the regulatory context.

As of August 26, 2026, there is not yet conclusive randomized evidence that selective pharmacological lowering of Lp(a) reduces cardiovascular events. Pelacarsen, olpasiran, lepodisiran, and other antisense or siRNA approaches have produced very large reductions in concentration, but their respective outcome trials have been completed or are ongoing without a definitive cardiovascular result having been published for the first major outcomes study; these therapies must therefore be regarded as highly promising prospects, not as already validated substitutes for standard prevention.
In patients at high or very high risk with persistently elevated triglycerides despite statin therapy, icosapent ethyl at a dose of 2 g twice daily may be considered in the setting specified by European guidelines when fasting triglycerides are approximately 135 to 499 mg/dL. The documented benefit of this specific product must not automatically be extrapolated to generic fish oil supplements or any mixture of omega-3 fatty acids.

Blood pressure control reduces coronary events, stroke, and heart failure. ACE inhibitors or angiotensin receptor blockers are particularly indicated in the presence of hypertension, diabetes, kidney disease, ventricular dysfunction, or other specific indications. The target must be individualized by considering age, tolerance, risk of hypotension, perfusion, and comorbidities, while generally pursuing intensive control when well tolerated.
In type 2 diabetes associated with coronary artery disease, treatment cannot be limited to HbA1c. SGLT2 inhibitors and GLP-1 receptor agonists with documented cardiovascular benefit must be selected on the basis of the patient's profile, indications, and comorbidities. The favorable effects of these classes include metabolic, hemodynamic, and renal mechanisms and, for some drugs, a substantial reduction in body weight.

In patients with overweight or obesity and established cardiovascular disease, management of adiposity has become an integral part of secondary prevention. The SELECT trial demonstrated that semaglutide 2.4 mg weekly reduces major cardiovascular events in adults with overweight or obesity and preexisting cardiovascular disease without diabetes, evidence that has changed the concept of obesity from a simple associated factor to a cardiovascular therapeutic target.
Antiplatelet therapy must be distinguished between primary prevention and clinically documented disease. Aspirin is not routinely indicated in all individuals who have risk factors or minimal subclinical calcification, because the ischemic benefit must be balanced against bleeding risk. In clinically significant obstructive atherosclerotic coronary artery disease and in secondary prevention, by contrast, antiplatelet therapy has an established role.

In patients with a previous infarction or remote PCI, the ESC generally recommends aspirin 75-100 mg daily over the long term after the period of dual antiplatelet therapy; clopidogrel 75 mg daily is an effective alternative. Even in patients without a previous infarction or revascularization but with significant obstructive coronary artery disease, low-dose aspirin is recommended in the absence of relevant contraindications.
After elective PCI for chronic coronary syndrome, a period of DAPT, generally with aspirin and clopidogrel, is used; its duration is tailored to the balance between ischemic and bleeding risk and commonly ranges from one to six months in modern algorithms. Subsequent antithrombotic treatment must be individualized according to patient, procedural, and stent characteristics and bleeding risk.

After acute coronary syndrome, in the absence of high bleeding risk or other reasons to modify the regimen, contemporary guidelines maintain approximately 12 months of DAPT with aspirin and a P2Y12 inhibitor as the reference strategy, favoring ticagrelor or prasugrel over clopidogrel in appropriate patients undergoing PCI. Abbreviated strategies, de-escalation, or P2Y12 monotherapy may be used in selected patients to reduce bleeding risk.
In patients with persistently high ischemic risk and low bleeding risk, intensification of antithrombotic therapy beyond the standard phase may be considered. Validated options include, in selected settings, aspirin combined with ticagrelor 60 mg twice daily after a previous infarction or aspirin combined with rivaroxaban 2.5 mg twice daily in high-risk coronary or polyvascular disease. The ischemic benefit must always be weighed against the increase in major bleeding.

Demonstration that inflammation constitutes a modifiable residual risk has introduced anti-inflammatory therapy into coronary prevention. CANTOS demonstrated that IL-1β inhibition with canakinumab can reduce events independently of lipid lowering, but the drug has not become a routine treatment for atherosclerosis because of its overall risk profile, costs, and regulatory indications.
Low-dose colchicine, by contrast, has demonstrated a reduction in events both after infarction and in chronic coronary disease. The 2024 ESC guidelines indicate that colchicine 0.5 mg/day should be considered in patients with chronic coronary syndrome and atherosclerosis to reduce infarction, stroke, and the need for revascularization, with assessment of kidney and liver function, tolerability, and possible drug interactions.

Antianginal drugs reduce symptoms but must not be confused with therapy that modifies the atherosclerotic process. Beta-blockers and calcium channel blockers are common choices, selected on the basis of heart rate, blood pressure, ventricular function, and comorbidities. Long-acting nitrates, ranolazine, and other agents may be added or substituted when necessary. Sublingual nitrate remains useful for rapid control of an anginal episode.
The prognostic benefit of beta-blockers depends on the context. They are fundamental in many situations involving ventricular dysfunction, heart failure, or other specific indications; an indefinite preventive benefit should not, however, automatically be attributed to all patients with stable coronary artery disease and normal ventricular function merely because they have atherosclerosis.

Revascularization is indicated to improve symptoms when ischemia due to significant stenoses persists despite adequate medical therapy and in specific anatomies or conditions in which it may improve prognosis. The decision must integrate anatomy, physiology, ventricular function, diabetes, disease complexity, operative risk, the possibility of achieving complete revascularization, and the patient's informed preferences.
In left main disease and complex multivessel disease, bypass surgery retains a fundamental role. In patients with complex anatomy, diabetes, and multivessel disease, CABG may offer advantages over PCI, whereas in less complex anatomy PCI may be an appropriate alternative. The comparison should be made by the Heart Team when the choice is not evident.

In chronic disease without significant left main involvement and with preserved ventricular function, revascularization must not be presented as a "cure for atherosclerosis." Contemporary studies have shown that an initial invasive strategy does not automatically provide a survival advantage over optimal medical therapy in all stable patients, although it offers better angina control in symptomatic individuals and has a prognostic indication in specific anatomical subgroups.
In acute coronary syndrome, revascularization has a different purpose: to rapidly restore perfusion to a vessel affected by acute thrombosis and prevent further necrosis. In patients with STEMI, primary PCI is the preferred reperfusion strategy when it can be performed within the recommended time frames; in NSTE-ACS, the urgency of the invasive approach depends on the clinical and hemodynamic risk profile.

Intracoronary imaging improves understanding of the lesion and optimization of PCI in complex anatomy. OCT can identify mechanisms such as rupture, erosion, calcium, and stent complications; IVUS is particularly useful in defining vessel dimensions, plaque burden, and optimizing complex interventions. Imaging guidance does not, however, replace the need for an appropriate indication for revascularization.
Focal preventive treatment of a high-risk nonculprit plaque, for example through preventive stenting, is the subject of intensive research. Recent studies have demonstrated that the concept is technically feasible in selected populations, but identification of a plaque with high-risk features does not currently constitute a general indication for prophylactic stent implantation. Systemic therapy remains the standard for the vast majority of plaques not responsible for events.

Follow-up must verify achievement and maintenance of lipid and blood pressure targets, glycemic control, smoking cessation, physical activity, body weight, adherence, and tolerability. Poor adherence is one of the principal causes of residual risk that appears "resistant" to therapy. Before classifying a treatment as ineffective, it is therefore necessary to verify the dose actually taken, treatment persistence, and interactions.
Prognosis depends much more on the overall risk burden than on the mere presence of a single stenosis. Multivessel disease, left main disease, high plaque burden, previous infarction, ventricular dysfunction, diabetes, kidney disease, peripheral artery disease, elevated Lp(a), and persistent exposure to LDL or smoking identify patients at higher risk.

A CCTA demonstrating nonobstructive atherosclerosis must not be interpreted as showing "normal coronary arteries." Risk is lower than that associated with extensive obstructive disease but higher than in individuals without plaque, and it increases with overall burden. Early recognition of nonobstructive disease therefore creates an opportunity for prevention before clinically manifest ischemia or thrombosis develops.
A very large and sustained reduction in LDL may result in stabilization and, in some patients, modest regression of atheroma volume; however, it does not instantly eliminate the risk accumulated over decades of previous exposure; this explains the residual risk observed even in modern trials: residual lipid-related risk may be compounded by inflammation, Lp(a), remnants, thrombogenicity, diabetes, kidney disease, and a high, already established plaque burden.

The most effective prevention therefore remains prevention begun early. The cumulative relationship between exposure to apoB particles and atherosclerosis implies that lowering LDL before a high plaque burden develops may produce a greater lifetime benefit than beginning the same reduction after decades of exposure. Treatment of patients with established disease remains essential, but primordial and primary prevention has even greater potential to reduce the overall burden of disease.

Complications

The most common complication of chronic progression is an increase in atherosclerotic burden until a hemodynamically significant stenosis develops. Reduced coronary reserve produces ischemia when myocardial demand increases, causing angina, exertional dyspnea, and functional limitation. Progression may be slow and continuous or may proceed in steps through subclinical episodes of thrombosis and healing.
Diffuse disease may impair perfusion even without a single critical stenosis. Progressive pressure loss along diffusely atherosclerotic segments and concomitant endothelial dysfunction reduce the coronary tree's ability to increase flow during stress; this form may be particularly difficult to recognize by visual angiographic assessment alone.

The most important complication in prognostic terms is coronary atherothrombosis. Rupture, erosion, or an eruptive calcified nodule may cause rapid accumulation of platelets and fibrin. A partially occlusive thrombus may cause unstable ischemia or NSTEMI; persistent occlusion of an epicardial artery may cause an extensive infarction and, depending on the territory, STEMI.
Thrombosis may be transient and undergo spontaneous lysis. In these cases, the patient may have a brief ischemic episode or perceive no symptoms. Residual thrombus may become organized within the wall, contributing to plaque growth and creating the substrate for a subsequent, more severe stenosis. The same biology that produces acute events may therefore contribute to the apparently "chronic" progression of the disease.

When acute coronary atherothrombosis causes myocardial ischemia and necrosis, a primary myocardial infarction develops. The extent of necrosis depends on the site and duration of occlusion, territory at risk, collateral circulation, any preconditioning, metabolic demand, and speed of reperfusion. Injury may range from small subendocardial infarctions to extensive transmural necrosis.
Infarction may cause acute left ventricular failure. Loss of a critical amount of contractile myocardium reduces cardiac output and increases filling pressures, producing pulmonary congestion up to pulmonary edema. In the most severe cases, cardiogenic shock develops, characterized by systemic hypoperfusion and high mortality.

Acute ischemia profoundly alters myocardial electrophysiology. Regional differences in potential, conduction velocity, and refractoriness may cause ectopy, ventricular tachycardia, and ventricular fibrillation; these arrhythmias are among the principal mechanisms of sudden death in the early stages of infarction.
After healing, the fibrous scar may become a permanent substrate for reentry circuits. Monomorphic ventricular tachycardia may therefore occur months or years after an infarction, especially in patients with reduced ventricular function. Arrhythmic risk stratification and any indication for an implantable defibrillator depend on the clinical picture and ventricular function, not on the coronary plaque in isolation.

Extensive myocardial necrosis may result in ventricular remodeling, dilation, and a progressive decline in systolic function. Increased wall stress and neurohormonal activation promote further dilation and dysfunction, ultimately leading to ischemic cardiomyopathy and chronic heart failure.
Infarctions involving the papillary muscles or altering ventricular geometry may produce ischemic mitral regurgitation. In the acute phase, rupture, more typically of the posteromedial papillary muscle after an inferior infarction, may cause severe acute mitral regurgitation, pulmonary edema, and shock and constitutes a cardiac surgical emergency.

Transmural necrosis may cause ventricular septal rupture with an acute left-to-right shunt. The resulting right ventricular overload and reduction in systemic output may rapidly lead to shock. Septal rupture is now less common because of early reperfusion but remains an extremely serious complication.
Ventricular free-wall rupture may cause hemopericardium and cardiac tamponade, often with sudden hemodynamic deterioration or death. Contained forms may evolve into a ventricular pseudoaneurysm, a structure lacking the normal myocardial wall and at risk of subsequent rupture.

Post-infarction remodeling may produce a true ventricular aneurysm composed of thinned scar tissue. The aneurysm may cause heart failure, ventricular arrhythmias, and blood stasis. Reduced regional contractility, especially at the apex, promotes formation of a left ventricular thrombus.
A ventricular thrombus may embolize into the systemic circulation, causing ischemic stroke or peripheral embolism; this mechanism is distinct from coronary atherothrombosis but is an indirect consequence of a large atherothrombotic infarction. Risk depends on the location of the infarction, severity of akinesia, thrombus morphology, and other prothrombotic conditions.

Pericardial inflammation may develop in the days after a transmural infarction because inflammation extends to the epicardial surface. A late post-infarction autoimmune pericardial syndrome is now much less common; these complications must be differentiated from new ischemia when the patient again reports chest pain after the event.
Repeated infarctions, even small ones, may produce a progressive loss of viable myocardium. The end result may be an ischemic cardiomyopathy with chronic heart failure, arrhythmias, functional mitral regurgitation, and a substantial reduction in survival. Preventing new events is therefore fundamental even after successful revascularization.

A plaque or thrombus may generate distal microembolization of atherothrombotic material, with obstruction of the microcirculation and small foci of necrosis. During acute coronary syndromes and interventions on lesions rich in thrombus or atheroma, this phenomenon may contribute to microvascular obstruction and failure to achieve complete recovery of tissue blood flow despite angiographic reopening of the epicardial artery.
The no-reflow phenomenon after PCI results from a combination of microembolization, ischemia-reperfusion injury, edema, endothelial dysfunction, and microvascular vasoconstriction. It is associated with greater infarct size and worse prognosis. It is not simply persistent epicardial obstruction, because the treated vessel may appear patent while tissue perfusion remains severely impaired.

Progression may culminate in a chronic total coronary occlusion. The artery distal to the occlusion may be perfused through collaterals, but flow reserve often remains limited. Patients may have angina, ischemia, reduced ventricular function, or no evident symptoms. Treatment depends on symptoms, ischemia, viability, anatomy, and the likelihood of procedural success.
Severe calcification not only increases prognostic burden but also makes revascularization more complex. Calcium may prevent adequate stent expansion, increase the risk of dissection or other procedural complications, and require specific plaque-modification techniques. Planning with intracoronary imaging is particularly important in these lesions.

Coronary atherosclerosis is also frequently an expression of polyvascular disease. Carotid, aortic, and peripheral atherosclerosis are not a direct consequence of coronary plaque, but they share the same causal exposures. Their coexistence identifies a phenotype with a high systemic burden and a particularly high risk of infarction, stroke, and cardiovascular death.
An acute coronary syndrome does not eliminate risk after the culprit lesion has healed. Numerous nonculprit plaques remain in the coronary tree and may progress or become destabilized. The risk of recurrent events is particularly high in the period after ACS and persists over the long term, especially when LDL, blood pressure, diabetes, smoking, inflammation, or other determinants are not intensively controlled.

Even after PCI, there are treatment-specific complications, including stent thrombosis and restenosis, which must be distinguished from progression of native atherosclerosis. Stent thrombosis is a potentially catastrophic atherothrombotic/procedural event; restenosis results primarily from the proliferative response and, at very late stages, may be associated with neoatherosclerosis within the stent.
After coronary artery bypass grafting, native disease continues to progress and grafts may develop their own pathological processes. Vein grafts are susceptible to intimal hyperplasia and subsequent accelerated atherosclerosis, with possible stenosis, degeneration, and thrombosis. Surgical revascularization therefore does not reduce the need for intensive lipid-lowering and cardiovascular prevention.

The ultimate consequence of complications may be cardiovascular death through extensive infarction, shock, ventricular arrhythmia, a mechanical complication, or progressive heart failure. Individual risk is not determined by a single plaque feature, but by the integration of anatomical burden, biological activity, ventricular function, comorbidities, effectiveness of prevention, and timeliness of treatment of acute events.
The availability of potent lipid-lowering therapies, antiplatelet agents, selected anti-inflammatory strategies, modern revascularization, and intensive risk factor control has profoundly changed the prognosis of the disease. Nevertheless, the extremely high global burden of ischemic heart disease demonstrates that the principal complication of coronary atherosclerosis remains its ability to progress silently for decades before becoming manifest. Early identification and treatment of causal exposure therefore constitute the strategy with the greatest potential to definitively reduce its morbidity and mortality.