Acute Coronary Syndrome

Etiology

The most common mechanism underlying ACS is disruption of an atherosclerotic coronary plaque, either through rupture or erosion, which exposes thrombogenic subendothelial material to circulating blood and triggers platelet activation, aggregation, and thrombus formation. Nonatherosclerotic causes include coronary vasospasm, spontaneous coronary artery dissection (SCAD), coronary embolism, and myocardial bridging.[1] The INTERHEART study, a landmark case-control study of 15,152 cases across 52 countries, demonstrated that 9 modifiable risk factors account for over 90% of the population-attributable risk of myocardial infarction (MI) worldwide: abnormal lipids (ApoB/ApoA1 ratio), smoking, hypertension, diabetes, abdominal obesity, psychosocial stress, low fruit and vegetable intake, physical inactivity, and excessive alcohol use.[6] Nonmodifiable risk factors include advancing age, male sex, and family history of premature coronary artery disease (MI in men younger than 55 or 65 in women). Cocaine and methamphetamine use can cause coronary vasospasm and should be considered in younger patients presenting with ACS.[1]

Epidemiology

Cardiovascular disease remains the leading cause of death worldwide, and more than 7 million people are diagnosed with ACS annually. In the United States alone, more than 1 million patients are hospitalized for ACS each year, with chest pain being among the most common reasons for emergency department visits. NSTEMI and unstable angina account for approximately 70% of ACS presentations, while STEMI accounts for approximately 30%.

The incidence of STEMI has been declining over recent decades, while the proportion of NSTEMI has increased. The median age at ACS presentation is 68, though ACS rates have been increasing among younger adults. Women experience their first MI approximately 9 years later than men (median age 65 vs 56), largely explained by differences in risk factor burden at younger ages.[1][7]

Pathophysiology

The clinical spectrum of ACS is unified by the sudden reduction of coronary blood flow, but the underlying mechanisms vary significantly across distinct pathogenetic pathways.[1]

Type 1 MI

The central event in type 1 MI is disruption of a coronary atherosclerotic plaque, which exposes thrombogenic subendothelial material to circulating blood and triggers platelet activation, aggregation, and thrombus formation. Plaque rupture, characterized by fissuring of a thin fibrous cap overlying a lipid-rich necrotic core infiltrated by activated macrophages, is the most common mechanism. Less commonly, plaque erosion occurs, in which a thrombus forms on a proteoglycan-rich, endothelium-denuded surface without frank cap disruption; this mechanism tends to produce platelet-rich rather than fibrin-rich thrombi.

The clinical and electrocardiographic (ECG) presentation depends directly on the degree of vessel occlusion. When the resulting thrombus completely occludes the coronary artery, transmural ischemia produces ST-segment elevation on ECG (STEMI). Conversely, partial or transient occlusion causes subendocardial ischemia, which may present as NSTEMI or unstable angina. The clinical distinction between NSTEMI and unstable angina depends entirely on whether ischemia is prolonged enough to cause myocardial necrosis, as evidenced by elevated cardiac troponin levels.

Type 2 MI

Myocardial ischemia results from a critical mismatch between myocardial oxygen supply and demand, occurring independently of acute plaque disruption. This imbalance is typically triggered by systemic stressors such as tachyarrhythmia, hypotension, severe anemia, or respiratory failure, and it occurs frequently in the setting of underlying stable coronary artery disease.

Type 3 MI

This type represents a distinct clinical scenario where patients experience a fatal MI before cardiac biomarkers can be drawn or before detectable elevations appear in the blood. These patients typically present with classic ischemic symptoms or new ischemic ECG changes (such as new ST-segment elevation or a new left bundle branch block) but experience sudden cardiac death, often secondary to a fatal ventricular arrhythmia, before a definitive biochemical diagnosis can be established.

Type 4 MI

This type is explicitly linked to percutaneous coronary interventions (PCI) and is further categorized into 3 distinct subtypes based on the underlying mechanical or anatomical cause:

• Type 4a MI
  • This is defined as a procedure-related MI occurring within 48 hours of an index PCI. 
  • This type is pathologically driven by severe procedural complications, such as side-branch occlusion, disruption of collateral flow, distal embolization of plaque fragments, or transient dissection of the target vessel, resulting in significant elevations of cardiac troponin.
• Type 4b MI
  • This is attributed directly to stent or scaffold thrombosis.
  • Pathophysiologically, this occurs when an acute, subacute, or late thrombus forms within the deployed stent, leading to sudden vessel occlusion.
  • This is confirmed by coronary angiography or autopsy findings.
• Type 4c MI
  • This is defined as restenosis-associated MI.
  • This occurs when an infarction is linked to progressive, severe in-stent restenosis or a complex neointimal plaque recurrence within the treated segment, rather than an acute thrombotic occlusion.

Type 5 MI

This type is associated directly with coronary artery bypass graft surgery, occurring within 48 hours of the operative procedure. The underlying pathology involves perioperative myocardial injury resulting from prolonged global ischemia during cardiopulmonary bypass, inadequate myocardial protection, surgical manipulation of the heart, or acute graft occlusion (either technical or thrombotic) of a newly placed arterial or venous conduit. Due to the baseline myocardial trauma inherent to cardiac surgery, type 5 MI requires a much higher threshold of cardiac troponin elevation, accompanied by new structural or ECG evidence of ischemia, to confirm the diagnosis.

History and Physical

The hallmark symptom of ACS is substernal chest pressure or heaviness, which patients often describe as a band-like sensation. This feeling is often addressed as discomfort rather than pain. The discomfort often radiates to the jaw, neck, either shoulder, or left arm, and lasts 10 minutes or longer. This symptom may be accompanied by dyspnea, diaphoresis, nausea, or lightheadedness. Unexplained new-onset exertional dyspnea is the most common anginal equivalent. Atypical presentations, including isolated dyspnea, epigastric pain, or fatigue without chest pain, are more common in women, older adults, and patients with diabetes or renal insufficiency. Features not characteristic of ischemia include pleuritic-type pain, pain reproduced by palpation, and very brief episodes lasting seconds, although these do not entirely exclude ACS.[4]

The physical examination should focus on identifying hemodynamic compromise and potential alternative diagnoses. Diaphoresis and general distress are commonly observed. Heart sounds are frequently normal, though an S3 gallop or new murmur may indicate ventricular dysfunction or papillary muscle involvement. Crackles on lung examination or bilateral leg edema suggest associated heart failure. Findings such as pulse differentials between extremities (aortic dissection), a pericardial friction rub (pericarditis), unilaterally absent breath sounds (pneumothorax), or unilateral leg swelling (deep venous thrombosis leading to pulmonary embolism) should prompt consideration of alternative diagnoses.[1]

Evaluation

A 12-lead ECG should be obtained and interpreted within 10 minutes of first medical contact in any patient with suspected ACS, as recommended by the 2025 ACC/AHA guidelines. ST-segment elevations in 2 or more contiguous leads (1 mm or greater in all leads except V2–V3, where sex- and age-specific criteria apply) indicate STEMI. They should prompt immediate activation of the cardiac catheterization laboratory at PCI-capable centers. ST depressions, T-wave inversions, or a normal ECG with ongoing symptoms suggest NSTE-ACS; serial ECGs should be obtained if the initial tracing is nondiagnostic. 

High-sensitivity cardiac troponin (hs-cTn) is the preferred biomarker for detecting myocardial injury.[4] NSTEMI is distinguished from unstable angina by troponin elevation above the 99th percentile with a rise and/or fall pattern. Clinicians should be aware of the specific troponin assay used at their facility and its clinically significant delta. The ESC-endorsed 0-hour/1-hour hs-cTn algorithm can safely identify low-risk patients for early discharge.

A complete vital signs assessment—including blood pressure, heart rate, and oxygen saturation—must be performed immediately, along with a focused physical exam to evaluate peripheral perfusion and skin temperature. Clinicians should aggressively screen for signs of concurrent heart failure or shock. The presentation of hypotension, tachycardia, and pulmonary edema, coupled with cool, clammy extremities, is an ominous indicator of cardiogenic shock in the setting of ACS. This clinical picture demands urgent intervention, including immediate stabilization and prompt consideration for mechanical circulatory support.[8]

Additional workup should be performed promptly in these patients to rule out life-threatening mimickers of ACS and to identify any absolute or relative contraindications to therapy. This includes a chest radiograph to rule out pulmonary edema, pneumothorax, or mediastinal widening suggestive of aortic dissection. Notably, aortic dissection and pulmonary embolism are 2 critical differential diagnoses that must be kept in mind; if clinical suspicion is high, a prompt computed tomography chest angiogram should be performed.

Laboratory evaluation, including a basic metabolic panel, complete blood count, and coagulation studies, should be ordered to check for metabolic derangements, renal insufficiency, acute anemia, or underlying coagulopathies. A lipid panel and hemoglobin A1c should also be obtained to assess long-term cardiovascular risk factors. Point-of-care echocardiography should be performed whenever available to evaluate left ventricular function, look for regional wall motion abnormalities, and detect acute mechanical complications [1][4].

Risk stratification tools guide disposition and the intensity of management. They include: 

• HEART score
  • This is validated for undifferentiated chest pain in the emergency department. This score helps determine which patients with chest pain should be admitted and which patients could be discharged safely with recommended outpatient follow-up; patients scoring 0 to 3 with negative serial troponins can be safely discharged with outpatient follow-up.[9]
• TIMI Risk Score for Unstable Angina/NSTEMI 
  • This predicts 14-day all-cause mortality, new or recurrent MI, or the need for urgent revascularization in those with non–STEMI ACS. In practice, it helps decide between an early invasive strategy and a conservative ischemia-guided strategy.[3] A substudy of PRISM-PLUS demonstrated that patients with TIMI scores of 5 to 7 were significantly more likely to have severe culprit stenosis, multivessel disease, or left main coronary artery disease on angiography.[3] 
• GRACE score 
  • This is an extensively validated and guideline-endorsed tool for risk stratification in acute coronary syndromes. This score incorporates 8 variables, including readily available clinical, ECG, and laboratory data, and it provides a reliable estimate of short and long-term mortality. Using this helps clinicians identify high-risk individuals who benefit most from early invasive strategies and intensified medical therapy.[10] 

Treatment / Management

Initial Management for All ACS

All patients with suspected ACS should receive continuous cardiac monitoring, aspirin 162 to 325 mg (chewed), and parenteral anticoagulation. Supplemental oxygen is indicated only when saturation is less than 90%. Sublingual nitroglycerin is administered to relieve ischemic pain. Still, it should be avoided in suspected right ventricular infarction, hypotension (systolic blood pressure <90 mm Hg), or recent phosphodiesterase inhibitor use within the past 48 hours. Intravenous morphine may be used for severe pain not responsive to nitrates, but should not be administered routinely.

The 2025 ACC/AHA guidelines recommend DAPT with aspirin and a P2Y12 inhibitor for all patients with ACS. Ticagrelor or prasugrel is recommended in preference to clopidogrel in patients undergoing PCI, based on the PLATO and TRITON-TIMI 38 trials, which demonstrated more potent platelet inhibition and reduced major adverse cardiovascular events compared with clopidogrel. Prasugrel is contraindicated in patients with prior stroke or transient ischemic attack, as the TRITON-TIMI 38 trial demonstrated net harm in this subgroup. In patients with NSTE-ACS scheduled for an invasive strategy with angiography anticipated to be more than 24 hours away, upstream treatment with clopidogrel or ticagrelor may be considered.[4](A1)

STEMI: Reperfusion Strategy

Primary PCI with drug-eluting stent placement is the preferred reperfusion strategy for STEMI. The 2025 guidelines recommend a target first medical contact-to-device time of 90 minutes or less at PCI-capable hospitals and 120 minutes or less when transfer is required. Radial access is preferred over femoral access to reduce bleeding, vascular complications, and death. Intracoronary imaging is recommended to guide PCI in patients with complex coronary lesions.

A strategy of complete revascularization is now recommended (class 1) in hemodynamically stable individuals with STEMI and multivessel disease, with PCI of significant nonculprit stenoses performed either during the index procedure or staged, with some preference toward single-procedure multivessel PCI. In patients with cardiogenic shock, emergency revascularization of the culprit vessel is indicated. Still, routine PCI of noninfarct-related arteries at the time of primary PCI is not recommended (class 3: harm).

When PCI cannot be achieved within 120 minutes, fibrinolytic therapy should be administered within 30 minutes of first medical contact (door-to-needle time), followed by transfer for angiography within 3 to 24 hours (pharmacoinvasive strategy). The STREAM trial demonstrated that prehospital fibrinolysis followed by timely PCI yielded similar 30-day composite outcomes and 1-year mortality compared with primary PCI in early presenters (symptoms within 3 hours) who were unable to receive PCI within 1 hour. Tenecteplase is the preferred fibrinolytic agent due to superior fibrin specificity, convenient bolus dosing, and reduced noncerebral bleeding compared with alteplase.

Half-dose tenecteplase is recommended for patients aged 75 and older to reduce the risk of intracranial hemorrhage. Clopidogrel is the only recommended P2Y12 inhibitor for patients receiving fibrinolysis; ticagrelor and prasugrel should not be used in this setting due to insufficient safety data and a potential increase in bleeding risk. Absolute contraindications to fibrinolysis include prior intracranial hemorrhage, ischemic stroke within 3 months, central nervous system neoplasm or arteriovenous malformation, suspected aortic dissection, active bleeding or bleeding diathesis, and severe uncontrolled hypertension unresponsive to emergent therapy.[4](A1)

NSTEMI/Unstable Angina: Invasive vs Selective Invasive Strategy

The 2025 ACC/AHA guidelines recommend an invasive approach with the intent to revascularize during hospitalization for patients with intermediate- or high-risk NSTE-ACS (class 1, level A). For low-risk individuals, either a routine invasive or a selective invasive approach is recommended. Risk stratification guides timing: immediate angiography (within 2 hours) for refractory angina, hemodynamic or electrical instability, or mechanical complications; early angiography (within 24 hours) for high-risk patients (GRACE score >140); and angiography before hospital discharge for remaining patients intended for invasive evaluation. The TIMACS trial demonstrated that early angiography within 24 hours reduced recurrent ischemia in high-risk patients (GRACE score >140), and the VERDICT trial showed similar findings with early angiography within 12 hours.

Complete revascularization is also recommended in NSTE-ACS (class 1). The choice between multivessel PCI and coronary artery bypass grafting (CABG) should be based on the complexity of coronary artery disease and comorbid conditions. CABG is preferred in patients with multivessel disease, complex anatomy, or diabetes with multivessel CAD.[4](A1)

The TIMI risk score further guides management in NSTE-ACS. The TACTICS-TIMI 18 trial demonstrated that intermediate- and high-risk individuals (TIMI score 3 or higher) who underwent early invasive intervention had significantly reduced rates of death, nonfatal MI, and rehospitalization compared with conservative management. In contrast, low-risk individuals (TIMI score 0 to 2) showed no significant difference between strategies.[3](A1)

Anticoagulation in ACS

Parenteral anticoagulation is indicated in all patients with ACS. Options include unfractionated heparin, enoxaparin, fondaparinux, and bivalirudin. For patients with STEMI undergoing primary PCI, unfractionated heparin is the preferred agent per the 2025 guidelines, though enoxaparin remains a reasonable alternative. Bivalirudin is reserved for patients with heparin-induced thrombocytopenia. For patients undergoing fibrinolysis, anticoagulation should continue until revascularization or for at least 48 hours up to 8 days if no revascularization is planned.

The ExTRACT-TIMI 25 trial demonstrated the benefit of enoxaparin over unfractionated heparin in this setting, though with an increased risk of noncerebral bleeding. For NSTE-ACS, the OASIS-5 trial demonstrated that fondaparinux was noninferior to enoxaparin in terms of efficacy and had a better bleeding profile. However, intraprocedural unfractionated heparin is required during PCI to prevent catheter-related thrombosis.[4](A1)

Adjunctive Medical Therapy

Beta-blockers should be initiated orally within 24 hours in hemodynamically stable individuals without contraindications (hypotension, acute heart failure, atrioventricular block, severe bradycardia). In patients treated with fibrinolysis, early administration of beta-blockers reduces the incidence of malignant ventricular arrhythmias. Carvedilol is preferred in left ventricular dysfunction, based on the CAPRICORN trial.

High-intensity statin therapy (atorvastatin 80 mg or rosuvastatin 20–40 mg) is recommended for all patients with ACS (class 1, level A). A key change in the 2025 guidelines is the option to initiate concurrent ezetimibe with statin therapy (class 2b). For patients already on maximally tolerated statin with LDL-C 70 mg/dL or higher, adding a nonstatin lipid-lowering agent (ezetimibe, evolocumab, alirocumab, inclisiran, or bempedoic acid) is recommended (class 1). The IMPROVE-IT trial demonstrated that adding ezetimibe to simvastatin after ACS resulted in a modest but significant reduction in MACE over 6 years. The FOURIER and ODYSSEY OUTCOMES trials demonstrated a 15% relative risk reduction in MACE with the addition of PCSK9 inhibitors to statin therapy.

ACE inhibitors or angiotensin receptor blockers (ARBs) are indicated for patients with a left ventricular ejection fraction of 40% or less, hypertension, diabetes, or anterior STEMI. Mineralocorticoid receptor antagonists (eplerenone or spironolactone) are added when the left ventricular ejection fraction is 40 percent or less with heart failure or diabetes, provided renal function is adequate, and hyperkalemia is absent.[4](A1)

DAPT Duration and Patients on Anticoagulation

DAPT with aspirin and a P2Y12 inhibitor for at least 12 months is the default strategy for patients not at high bleeding risk (class 1, level A). A major new recommendation in the 2025 guidelines is that, in patients who have tolerated DAPT with ticagrelor, transitioning to ticagrelor monotherapy at 1 month or more after PCI is useful for reducing bleeding risk (class 1, level A). This recommendation is supported by several randomized trials that consistently show that aspirin withdrawal followed by ticagrelor monotherapy reduces bleeding without increasing MACE. De-escalation of DAPT by switching from ticagrelor or prasugrel to clopidogrel after 1 month may be reasonable to reduce bleeding risk (class 2b).

For individuals with ACS requiring long-term oral anticoagulation (eg, atrial fibrillation), aspirin should be discontinued after 1 to 4 weeks of triple antithrombotic therapy, with continued use of a P2Y12 inhibitor (preferably clopidogrel) and an oral anticoagulant to reduce bleeding risk (class 1). A proton pump inhibitor is recommended for patients at risk of gastrointestinal bleeding who are on DAPT, oral anticoagulants, or both (class 1, level A).[4](A1)

Cardiogenic Shock

Cardiogenic shock complicates approximately 10% of STEMI cases and carries an early mortality rate of 40% to 50%. Emergency culprit-vessel PCI is indicated. The DanGer-SHOCK trial demonstrated that in selected patients with STEMI and severe cardiogenic shock (SCAI stages C, D, or E), use of a microaxial intravascular flow pump (Impella) reduced 180-day all-cause mortality by 26% (absolute risk reduction 12.7%, number needed to treat of 8), though with increased complications including bleeding, limb ischemia, and renal replacement therapy.

Based on this trial, the 2025 guidelines provide a class 2a recommendation for the use of microaxial flow pumps in selected STEMI patients with severe or refractory cardiogenic shock. Routine use of intra-aortic balloon pump (IABP) or venoarterial extracorporeal membrane oxygenation (VA-ECMO) is not recommended due to lack of survival benefit (class 3: no benefit). In right ventricular infarction, nitrates, morphine, and diuretics should be avoided; volume expansion is the initial hemodynamic strategy.[1]

Differential Diagnosis

The differential diagnosis of ACS is broad and includes both life-threatening and benign conditions that can mimic ischemic chest pain. A systematic approach is essential to avoid missed diagnoses and unnecessary interventions.[11]

Cardiovascular causes include:

• Acute pericarditis
  • This classically presents with sharp pleuritic chest pain improved by sitting forward and diffuse ST elevations on ECG.
• Myocarditis
  • This may present with troponin elevation and chest pain, but often follows a viral prodrome.
• Aortic dissection suggested by tearing pain radiating to the back, pulse differentials, or mediastinal widening on chest radiograph
• Hypertensive emergency with acute heart failure
• Takotsubo cardiomyopathy
  • This can closely mimic STEMI with ST elevations and wall motion abnormalities, typically in the setting of emotional or physical stress.[12][13]

Pulmonary causes include:

• Pulmonary embolism should be considered in patients with pleuritic chest pain, dyspnea, tachycardia, and risk factors for venous thromboembolism.
• Pneumothorax is identified by absent breath sounds and confirmed on chest radiograph.
• Pneumonia can present with pleuritic pain and fever.[12]

Gastrointestinal causes include:

• Esophageal spasm
• Gastroesophageal reflux disease
• Esophagitis
• Peptic ulcer disease
• Pancreatitis
• All can present with epigastric or substernal pain that may be difficult to distinguish from ACS on history alone [11]

Musculoskeletal causes include:

• Costochondritis
• Chest wall pain
• These are common; often reproducible with palpation, although reproducibility does not entirely exclude ACS [14]

Psychiatric causes include:

• Panic disorder
• Anxiety
• These can produce chest pain, dyspnea, and diaphoresis. These remain diagnoses of exclusion after life-threatening etiologies have been ruled out.[11]

Prognosis

The prognosis in ACS depends on clinical subtype, timeliness of reperfusion, extent of myocardial damage, and patient risk profile. Primary PCI confers a long-term survival advantage over fibrinolysis; a 16-year follow-up of the DANAMI-2 trial demonstrated significantly lower cardiac mortality with PCI compared with fibrinolysis (18.3% vs 22.7%). Each 10-minute reduction in door-to-balloon time is independently associated with lower in-hospital mortality.

Risk scores are strong prognostic tools. The TIMI risk score predicts a stepwise increase in 14-day adverse events from 4.7% (score 0 to 1) to 40.9% (score 6 to 7).[3] The GRACE score predicts in-hospital and 6-month mortality and identifies patients benefiting most from early invasive management.[4] Key predictors of poor prognosis include advanced age, diabetes, chronic kidney disease, reduced left ventricular ejection fraction, and cardiogenic shock. Short-term mortality in NSTEMI may be lower than STEMI, but as follow-up extends to 2 years, mortality rates become comparable.[1]

Complications

Recurrent ischemia or reinfarction may occur in patients with incomplete revascularization or stent thrombosis. The TIMI 11B and ESSENCE trials demonstrated that nearly one-third of MIs and half of deaths occur after the first week of presentation, with approximately a quarter of adverse cardiac events occurring within 6 weeks following discharge.[3] Mechanical complications include ventricular septal defect, papillary muscle rupture with acute mitral regurgitation, and free wall rupture with tamponade, all of which typically present within the first week and require emergent surgical intervention. Short-term mechanical circulatory support devices are reasonable for hemodynamic stabilization as a bridge to surgery in these patients (class 2a).

Arrhythmias range from ventricular fibrillation and sustained ventricular tachycardia in the acute phase to high-degree atrioventricular block. Right ventricular infarction may present with hypotension and requires volume resuscitation while avoiding nitrates and diuretics. Postinfarction pericarditis can occur early (within days) or as Dressler syndrome weeks later. Heart failure may develop acutely or as chronic ischemic cardiomyopathy. Treatment-related complications include bleeding from antiplatelet and anticoagulant therapy, with intracranial hemorrhage being the most feared complication of fibrinolysis.[1][4]