Coronary artery disease

Article written and reviewed by Dr Luca Moretti

Coronary artery diseases comprise anatomical and functional conditions affecting the epicardial coronary arteries, their branches, and the intramyocardial microcirculation. The common clinical denominator is the possibility that coronary blood flow becomes inadequate for the metabolic needs of the myocardium, but causes, mechanisms, and course are profoundly heterogeneous. The most common form is coronary atherosclerosis, which may remain subclinical, cause progressive stenosis, or become complicated by thrombosis. Not all coronary artery diseases are atherosclerotic, and not all ischemia results from visible epicardial narrowing.

It is useful to distinguish three concepts that are often conflated in everyday language. Coronary artery disease describes a structural lesion or functional disorder of the coronary vessels. Ischemic heart disease indicates myocardial injury or dysfunction caused by an oxygen supply insufficient for demand. Coronary syndrome, by contrast, describes a recognizable acute or chronic clinical presentation through which the disease manifests. Consequently, plaque may exist without ischemia, ischemia may occur without obstructive stenosis, and an increase in troponin may represent nonischemic myocardial injury.
Acute coronary syndromes include myocardial infarction with persistent ST-segment elevation, myocardial infarction without ST-segment elevation, and unstable angina. They most often result from atherothrombosis but may also be caused by spontaneous coronary artery dissection, embolism, prolonged vasospasm, or other causes. Chronic coronary syndromes include patients with suspected or known stable coronary artery disease, previous infarction or revascularization, ventricular dysfunction of ischemic origin, and persistent angina or ischemia.

A distinct chapter is represented by angina and ischemia with nonobstructive coronary arteries. ANOCA and INOCA phenotypes primarily include microvascular dysfunction and vasospasm, often coexisting with modest diffuse atherosclerosis. Their prognosis is not necessarily benign, and the absence of major stenoses does not justify automatically classifying symptoms as noncardiac.
Nonatherosclerotic coronary artery diseases include spontaneous dissection, embolism, thrombosis unrelated to plaque rupture, vasculitis, aneurysms, ectasia, congenital anomalies, and clinically relevant myocardial bridging. Some affect populations with a profile very different from that of atherosclerotic coronary artery disease and require specific diagnostic and therapeutic strategies.

Ischemic heart disease remains one of the leading causes of death and disability worldwide. The true impact of coronary artery disease is even greater than that recorded by clinical events because a considerable amount of nonobstructive atherosclerosis, silent ischemia, and microvascular dysfunction remains undiagnosed. Population aging, survival after infarction, and the global increase in diabetes, obesity, and kidney disease increase the number of people living long term with a chronic coronary syndrome.

Etiology, risk factors, pathogenesis, and pathophysiology

Coronary perfusion must continuously adapt to the heart's oxygen consumption. Unlike other organs, the myocardium already extracts a high proportion of the oxygen contained in arterial blood at rest; when demand increases, increased supply therefore depends primarily on increased blood flow. Regulation involves epicardial conductance arteries, prearterioles and resistance arterioles, the endothelium, local metabolites, myogenic control, the autonomic nervous system, and extravascular compression. Ischemia develops when one or more of these levels fail to provide adequate supply.
The dominant cause in the adult population is atherosclerosis, driven by cumulative exposure to apolipoprotein B-containing lipoproteins and modulated by blood pressure, smoking, diabetes, kidney function, adiposity, inflammation, genetic predisposition, and the environment. Atherosclerotic burden does not coincide with the severity of a single stenosis. Diffuse disease and expansive remodeling may leave the lumen apparently preserved while being associated with future risk.

An epicardial stenosis progressively impairs the ability to increase blood flow. At rest, dilation of distal arterioles may compensate for moderate pressure loss; during exertion, when this reserve is exhausted, subendocardial perfusion becomes vulnerable. Tachycardia and increased blood pressure raise demand, while tachycardia shortens diastole, the phase during which most left ventricular perfusion occurs. Hypertrophy, increased end-diastolic pressure, and anemia may aggravate the imbalance.
In diffuse atherosclerotic disease, pressure loss is distributed along the vessel, and there may be no single lesion that explains the presentation. Serial stenoses interact; collateral circulation, perfused myocardial mass, and microvascular function further modify the relationship between anatomy and ischemia; for this reason, visual assessment of the percentage of stenosis does not replace physiology with FFR, iFR, or quantitative blood-flow measurements.

The acute transition is generally thrombotic. Plaque rupture, superficial erosion, and an eruptive calcified nodule expose or create a thrombogenic surface, with platelet adhesion and activation, thrombin generation, and fibrin deposition. The thrombus may be transient, partial, or occlusive. Presentation depends on site, duration, collateral circulation, distal embolization, associated vasoconstriction, and the amount of myocardium at risk, not solely on the lesion mechanism.
Epicardial vasospasm causes intense, reversible vasoconstriction that may critically reduce the lumen, often in the presence of smooth muscle hyperreactivity and endothelial dysfunction. It may cause angina at rest, transient ST-segment elevation, arrhythmias, or infarction. Smoking is an important associated factor; vasoconstrictor drugs and sympathomimetic substances may act as precipitants. Atherosclerosis and vasospasm may coexist.

Coronary microvascular dysfunction includes structural abnormalities, such as arteriolar remodeling and rarefaction, and functional abnormalities, such as reduced vasodilation or microvascular spasm. The mechanisms may reduce flow reserve, increase minimal resistance, cause heterogeneous ischemia, and generate angina without obstructive epicardial stenoses. These phenotypes are common in women but are not specific to the female sex.
Nonatherosclerotic causes act through different mechanisms. Spontaneous coronary artery dissection creates an intramural hematoma or false lumen that compresses the true lumen; embolism lodges thrombotic or other material in the coronary circulation; vasculitis inflames and damages the wall; aneurysms and ectasia promote stasis and thrombosis; congenital anomalies may cause dynamic compression, angulation, or a high-risk interarterial course. Myocardial bridging compresses an intramural segment during systole and becomes clinically significant in only a minority of individuals.

Ischemia initiates a metabolic and mechanical sequence. Reduced oxidative phosphorylation lowers ATP production, increases anaerobic glycolysis, lactate, and acidosis, and impairs ion pumps and diastolic relaxation. Regional systolic dysfunction, electrocardiographic changes, and symptoms follow; this ischemic cascade explains why perfusion or wall-motion abnormalities may precede angina and why a patient may have silent ischemia.
If blood flow is restored before necrosis, contractile dysfunction may persist for hours or days as stunned myocardium. A chronic or repeated reduction in perfusion may induce adaptation with a reversible reduction in contractility, termed hibernating myocardium, especially in territories with severe coronary artery disease and ventricular dysfunction. If ischemia is intense and prolonged, membrane integrity is lost, troponin is released, and necrosis develops.

Reperfusion injury, microembolization, edema, intramyocardial hemorrhage, and microvascular obstruction may prevent complete tissue perfusion despite reopening of the epicardial artery. The no-reflow phenomenon demonstrates that angiographic success and myocardial salvage are not equivalent. Final infarct size depends on time to vessel opening, the territory at risk, collaterals, and microcirculatory quality.

Classification, pathological anatomy, evolution, and phenotypes

A modern classification must integrate anatomy, mechanism, temporality, and myocardial consequence. The simple dichotomy between normal and stenotic coronary arteries is insufficient, as is the exclusive distinction between stable angina and infarction. Coronary artery diseases form a continuum in which the same patient may progress from a subclinical phase to a chronic syndrome, experience an acute event, and return to a chronic phase with modified residual risk.

• Epicardial atherosclerotic coronary artery disease: nonobstructive, focal obstructive, diffuse, multivessel, left main, or with chronic total occlusion.
• Vasomotor disorders: epicardial vasospasm, microvascular spasm, and impaired microvascular vasodilation.
• Nonatherosclerotic coronary artery diseases: dissection, embolism, primary thrombosis, vasculitis, aneurysm, ectasia, congenital anomaly, and myocardial bridging.
• Clinical consequences: subclinical atherosclerosis, ANOCA or INOCA, chronic coronary syndrome, acute coronary syndrome, silent ischemia, and ischemic cardiomyopathy.

Epicardial anatomy includes the right coronary artery and left main coronary artery, which usually divides into the left anterior descending and circumflex arteries. Dominance, variants of origin, collateral branches, and the distribution of myocardial mass explain why lesions with the same percentage of stenosis may have different consequences. A stenosis of the left main coronary artery or a proximal segment of the left anterior descending artery may subtend a much larger territory than a small-caliber distal lesion.
Atherosclerosis may present as calcific, fibrous, or lipid-rich plaque, with positive or negative remodeling. Coronary angiography visualizes the lumen and does not directly quantify the wall. CCTA, IVUS, and OCT show complementary aspects of burden and composition. Severe stenosis more strongly predicts a flow limitation, whereas thrombotic risk also depends on plaque biology and the patient's systemic susceptibility.

Chronic coronary syndromes do not indicate that the disease is static. The term emphasizes that the likelihood of events and symptoms changes over time with progression or regression of atheroma, control of risk factors, healing of subclinical ruptures, changes in microvascular function, and changes in ventricular function. After infarction, the patient reenters a chronic phase, but with initially high risk and a scar that may become an arrhythmic substrate.
Acute syndromes are initially classified by ECG as presentations with or without persistent ST-segment elevation. After troponin measurement and investigations, STEMI, NSTEMI, and unstable angina are distinguished; this classification guides the urgency of reperfusion but does not identify the mechanism with certainty: an acute occlusion may not produce the classic STEMI criteria, and ST-segment elevation may have noncoronary causes.

Infarction is further classified by the universal definition. The fifth universal definition distinguishes primary, secondary, and procedure-related myocardial infarction: primary infarction occurs spontaneously because of acute coronary pathology; secondary infarction results from another acute condition causing a supply-demand imbalance; procedure-related infarction results from a complication of a cardiac procedure within thirty days; this classification is not a mere semantic exercise because treatment and prognosis depend on the mechanism.
MINOCA is a working diagnosis, not a single disease. It requires myocardial injury, absence of epicardial stenoses of 50 percent or greater, and no immediately evident alternative explanation; it constitutes a working diagnosis requiring further investigation. Intracoronary imaging, magnetic resonance imaging, and functional testing may attribute the presentation to nonobstructive rupture or erosion, dissection, embolism, vasospasm, or microvascular dysfunction, or exclude infarction by identifying myocarditis or Takotsubo syndrome.

ANOCA describes angina with nonobstructive arteries, whereas INOCA requires evidence of ischemia. They may result from low coronary reserve, high microvascular resistance, epicardial or microvascular vasospasm, and combinations of these mechanisms. Angiography described as normal does not automatically measure microvascular function and does not exclude vasomotor coronary artery disease.
The anatomical course after revascularization requires further classification. Restenosis, stent thrombosis, and neoatherosclerosis may occur after PCI; after bypass surgery, vein grafts may develop intimal hyperplasia, accelerated atherosclerosis, and occlusion, whereas arterial grafts have greater average durability. Native disease continues in both cases and requires lifelong systemic therapy.

Clinical manifestations

The best-known manifestation is angina, but a large proportion of the disease remains asymptomatic. The history must describe the symptom without relying on the reductive label of typical or atypical pain. Site, quality, radiation, duration, precipitating factors, threshold of onset, resolution, frequency, course, and associated symptoms modify the likelihood of ischemia and urgency of assessment.
Chronic angina is often described as retrosternal pressure, heaviness, tightness, or burning precipitated by exercise, cold, or stress and resolving within a few minutes with rest or nitrate. It may radiate to the arms, shoulders, jaw, neck, back, or epigastrium. Reproducibility is not absolute: temperature, meals, anemia, blood pressure, and vascular tone may modify the threshold in the same patient.

Dyspnea, fatigue, and reduced exercise capacity may be ischemic equivalents. Ischemia impairs ventricular relaxation early and increases filling pressures; in patients with ventricular dysfunction, it may precipitate congestion. Older adults, people with diabetes, and patients with comorbidities may not recognize or report classic pain.
Vasospasm is often characterized by episodes at rest, sometimes at night or in the morning, with a rapid response to nitrates and transient ST-segment changes. Microvascular angina may occur during exertion or at rest, last longer, and respond variably to nitrates. No symptom profile is sufficiently specific to replace objective assessment.

An acute syndrome should be suspected with new pain at rest, rapid worsening of preexisting angina, a prolonged episode, sudden dyspnea, sweating, nausea, syncope, hypotension, or arrhythmia. Pain may be absent. An inferior infarction may present with nausea and bradycardia; a right ventricular infarction with hypotension and jugular venous distention; a large anterior infarction with pulmonary edema or shock.
Sudden cardiac death may be the first manifestation. In acute ischemia, electrical heterogeneity promotes ventricular tachycardia and fibrillation; in the chronic phase, post-infarction scar sustains reentry circuits. Syncope during chest pain, palpitations, or exertion is therefore a warning sign and requires urgent assessment.

Ischemic cardiomyopathy may present predominantly with heart failure: exertional dyspnea, orthopnea, edema, asthenia, and hospitalizations for congestion. Angina may be absent because of previous necrosis, denervation, or reduced activity. Ischemia, hibernating myocardium, and scar may coexist in the same ventricle, requiring integrated assessment of anatomy, function, and viability when the result may change treatment.
The history must investigate smoking, hypertension, diabetes, dyslipidemia, kidney disease, extracoronary atherosclerotic disease, a family history of premature events, previous infarction or revascularization, inflammatory diseases, therapies, and adherence. In young women with ACS, spontaneous dissection must be considered; in the presence of atrial fibrillation, valvular disease, endocarditis, or intracardiac thrombus, coronary embolism must be considered.

Physical examination is often normal in stable forms. It must assess vital signs, peripheral perfusion, signs of congestion, murmurs, a third or fourth heart sound, a pericardial friction rub, pulse asymmetry, and signs of systemic vascular disease. Hypotension, altered mental status, cold skin, oliguria, pulmonary edema, or a new systolic murmur after infarction suggests high-risk complications.
The differential diagnosis of pain includes aortic dissection, pulmonary embolism, pericarditis, myocarditis, aortic stenosis, hypertrophic cardiomyopathy, pneumothorax, esophageal disorders, and musculoskeletal pain. Some alternative diagnoses contraindicate treatments routinely used in ACS. Assessment must therefore be rapid but not blind to context.

Investigations and diagnosis

The first diagnostic branch is clinical stability. A patient with compatible acute symptoms must rapidly undergo a 12-lead ECG and high-sensitivity cardiac troponin testing, without delaying treatment when signs of occlusion or instability are present. In a chronic presentation, the risk factor-weighted clinical likelihood of obstructive coronary artery disease is instead estimated, and the examination capable of answering the anatomical or functional question is selected.
The ECG may show ST-segment elevation or depression, T-wave inversion, Q waves, arrhythmias, or conduction disturbances. A normal initial ECG does not exclude ACS and must be repeated during symptoms or clinical changes. Posterior and right-sided leads are useful when posterior or right ventricular infarction is suspected.

High-sensitivity troponin identifies myocardial injury, not its cause. A value above the sex-specific 99th percentile with a rising or falling pattern indicates acute injury; a diagnosis of infarction additionally requires evidence of ischemia. Sepsis, tachyarrhythmia, heart failure, pulmonary embolism, kidney failure, myocarditis, and many other conditions may increase it without primary myocardial infarction due to acute coronary pathology.

General clinical criteria of the fifth universal definition of myocardial infarction

• Presence of acute myocardial injury, documented by a rise or fall in cardiac troponin with at least one value above the sex-specific 99th percentile upper reference limit.
• Association with at least one of the following findings: symptoms or other signs of acute myocardial ischemia, including new ischemic ECG changes or new pathological Q waves; imaging evidence of acute coronary pathology; new loss of viable myocardium or a new regional wall-motion abnormality with a pattern consistent with an ischemic etiology.

Echocardiography assesses global and regional function, valves, the right ventricle, pressures, and mechanical complications. A new regional abnormality supports ischemia but does not by itself establish the timing of injury. It is essential at the bedside in shock or complicated pain; in chronic forms, it defines ejection fraction and alternative diagnoses.
CCTA has high rule-out power for obstructive coronary artery disease and also describes nonobstructive disease, burden, and certain plaque features. It is particularly suitable for many symptomatic patients with a low or intermediate clinical probability. Very extensive calcification, high heart rate, arrhythmias, kidney function, contrast allergy, and image quality influence appropriateness.

Functional stress imaging includes echocardiography, SPECT, PET, and magnetic resonance imaging. It identifies perfusion or contractile consequences, the extent of ischemia, and risk. PET and CMR can quantify or provide advanced characterization of flow and tissue; CMR distinguishes infarction, myocarditis, and Takotsubo syndrome and is central to the assessment of MINOCA.
The coronary artery calcium score quantifies calcific atherosclerosis and improves preventive risk stratification in selected individuals without known disease, but does not identify stenosis, noncalcified plaque, or ischemia and is not the test used to rule out ACS. Serial score progression does not directly measure statin efficacy, because statins may increase calcium density while reducing risk.

Invasive coronary angiography is indicated in high-risk acute syndromes, refractory symptoms, high-risk noninvasive findings, and when possible revascularization is anticipated. Intermediate stenoses must be assessed with FFR or nonhyperemic indices when their significance has not already been established. IVUS and OCT clarify morphology, dimensions, and complications and improve planning of complex procedures.
When no obstructive stenoses are present but angina or ischemia persists, the diagnostic process must continue. Coronary flow reserve, microvascular resistance, response to acetylcholine, and quantitative imaging make it possible to distinguish vasodilator dysfunction, microvascular spasm, and epicardial spasm. An endotype-specific diagnosis enables more rational treatment.

Prognostic stratification integrates anatomy, ventricular function, extent of ischemia, plaque burden, clinical presentation, troponin, ECG, age, diabetes, kidney function, and bleeding risk. In ACS, validated scores such as GRACE help estimate mortality and invasive timing; in chronic disease, left main disease, multivessel disease, impaired ventricular function, and uncontrolled symptoms identify high-risk scenarios.

Treatment and prognosis

Treatment combines event prevention, symptom control, myocardial protection, and correction of lesions when useful. No revascularization eliminates systemic disease. Smoking cessation, prescribed physical activity, a Mediterranean-style diet, weight control, adequate sleep, and medication adherence are permanent components, not a weak alternative to drugs.
Reducing atherogenic lipoproteins is fundamental in atherosclerotic coronary artery disease. A high-intensity statin at the maximum tolerated dose is the foundation; ezetimibe, PCSK9 antibodies, and bempedoic acid are added according to risk, distance from target, tolerability, and outcome evidence. European and United States guidelines converge on very low LDL-C in patients at very high risk, generally below 55 mg/dL.

Blood pressure, diabetes, and kidney disease require individualized treatment. ACE inhibitors or angiotensin receptor blockers are particularly useful when specific indications are present; SGLT2 inhibitors and GLP-1 receptor agonists with cardiovascular benefit reduce events in appropriate populations with diabetes, heart failure, kidney disease, or obesity. The choice must consider ventricular function, glomerular filtration rate, blood pressure, and comorbidities.
Antiplatelet therapy depends on context. Aspirin should not be prescribed to everyone with risk factors. In secondary prevention and clinically significant coronary artery disease, aspirin or clopidogrel is used long term; after ACS or PCI, a period of dual antiplatelet therapy is used, with duration and intensity balancing ischemic and bleeding risks. An indication for oral anticoagulation modifies the regimen and requires minimizing triple therapy.

Antianginal drugs are selected according to mechanism and hemodynamic profile. Beta-blockers and calcium channel blockers are common options; long-acting nitrates and ranolazine may be added. Calcium channel blockers and nitrates are central in vasospasm, whereas nonselective beta-blockers may worsen some presentations. In microvascular dysfunction, treatment must be guided by the endotype and includes risk-factor control, antianginal agents, and treatment of the vasomotor component.
Revascularization with PCI or CABG improves symptoms when a significant stenosis causes uncontrolled ischemia. It may improve prognosis in selected anatomical settings, including left main disease, complex multivessel disease, and some patients with ventricular dysfunction or diabetes. In stable patients without anatomical conditions excluded from the trials, ISCHEMIA showed that an initial invasive strategy does not automatically reduce mortality compared with optimal medical therapy, although it provides greater symptomatic benefit in patients with frequent angina.

In ACS, the priority is to restore flow and limit necrosis. In STEMI, primary PCI is preferred when promptly available; if the anticipated delay is excessive and the patient presents early without contraindications, fibrinolysis followed by transfer is an alternative. In NSTE-ACS, the invasive approach is urgent in the presence of instability and early in high-risk patients.
Cardiac rehabilitation after infarction, ACS, PCI, or CABG integrates supervised exercise, education, risk-factor control, psychological support, and treatment optimization. It reduces rehospitalizations and improves functional capacity and quality of life. The transition from hospital to community care, medication reconciliation, and early lipid assessment are crucial elements.

Prognosis ranges from a risk close to that of the population in some individuals without plaque to a very high risk in patients with recent ACS, multivessel disease, previous infarction, impaired ventricular function, diabetes, kidney disease, or peripheral artery disease. Absence of stenosis does not imply a normal prognosis when diffuse plaque, INOCA, or dissection is present.
Residual risk may be lipid-related, inflammatory, thrombotic, metabolic, or due to the anatomical burden already accumulated. Follow-up must verify measurable targets, tolerability and adherence, symptom recurrence, ventricular function, and new comorbidities. Repeating tests without a question capable of changing management exposes patients to incidental findings and unnecessary procedures.

Complications

Myocardial infarction is the principal complication of coronary artery disease. Necrosis may be limited or extensive, subendocardial or transmural, and involve the left ventricle, right ventricle, or both. Site and duration of occlusion, collateral circulation, and microcirculation determine residual function and death risk.
In the first hours, electrical instability may cause ventricular tachycardia, ventricular fibrillation, bradyarrhythmias, and atrioventricular blocks. Subsequently, scar and remodeling may sustain monomorphic ventricular arrhythmias. Arrhythmic risk depends primarily on ventricular function, scar extent, and clinical history.

An extensive infarction may cause acute heart failure, pulmonary edema, and cardiogenic shock. Reopening the culprit vessel is essential, but microvascular dysfunction, systemic inflammation, and multiorgan failure may perpetuate shock. In patients with multivessel disease and shock, initial PCI is generally limited to the culprit lesion.
Mechanical complications include free-wall rupture with tamponade, ventricular septal defect, and papillary muscle rupture with acute mitral regurgitation. They are less frequent in the reperfusion era but retain high mortality. A new murmur, sudden pulmonary edema, or hemodynamic deterioration after infarction requires immediate echocardiography and cardiac surgical assessment.

Remodeling may cause a true ventricular aneurysm, whereas a contained rupture produces a pseudoaneurysm with rupture risk. Apical akinesia and a large anterior infarction promote left ventricular thrombus, with possible cerebral or systemic embolism. CMR is more sensitive than noncontrast echocardiography for small apical thrombi.
Repeated infarctions, persistent ischemia, and myocardium that has not recovered lead to ischemic cardiomyopathy, functional mitral regurgitation, and chronic heart failure. Scar alters ventricular geometry and synchrony, while neurohormonal activation amplifies dilation and dysfunction. Heart failure therapy, prevention of new events, and selective revascularization must be integrated.

Early pericarditis, post-infarction syndrome, atrial arrhythmias, emboli, acute kidney injury, and bleeding complications of treatment may accompany ACS; the latter are prognostically relevant and require an antithrombotic strategy that considers age, weight, kidney function, previous bleeding, and the need for anticoagulation.
After PCI, dissection, perforation, no-reflow, contrast-associated kidney injury, stent thrombosis, and restenosis may occur. After CABG, perioperative ischemia, stroke, atrial fibrillation, and infections are observed, with graft degeneration over time. Technical optimization and secondary prevention reduce but do not eliminate these risks.

The most common long-term complication is recurrence: new angina, a new ACS, repeat revascularization, or progression to heart failure. Risk remains systemic because nonculprit plaques, the microcirculation, and other vascular territories are not corrected by treatment of a single lesion.
Early prevention is therefore part of the treatment of complications. Reducing exposure to LDL and apoB for many years, avoiding smoking, controlling blood pressure and diabetes, and addressing inequalities in access to care reduce not only the first infarction, but also the amount of myocardium lost, late heart failure, and sudden death.