Acute Coronary Syndromes (ACS)

Definition and Classification

Epidemiology

• ~1.2 million hospitalizations annually in the United States for ACS
• ~2/3 are NSTE-ACS

• 50% of NSTE-ACS patients are older than 65 years; nearly half are women

• Risk is higher with atherosclerosis risk factors, peripheral vascular disease, and chronic inflammatory conditions (rheumatoid arthritis, psoriasis, SLE, chronic infection)

Pathobiology

Type 1 vs. Type 2 MI

• Type 1 MI: Rupture or erosion of an atherosclerotic plaque → platelet aggregation → thrombus → reduced/absent coronary flow (the vast majority of ACS)
• Type 2 MI: Oxygen supply-demand mismatch without plaque rupture - caused by severe hypotension, anemia, hypoxemia, tachycardia, hypertension, or thyrotoxicosis. Treatment targets the underlying cause.

Plaque Rupture - The Central Event

1. Lipid deposition and inflammation: Oxidized LDL accumulates in the arterial wall, recruiting macrophages and T-lymphocytes to the plaque border
2. Fibrous cap degradation: Inflammatory cells secrete cytokines (TNF, IL-1, IFN-γ) that inhibit collagen synthesis, and enzymes (matrix metalloproteinases, cathepsins) that degrade collagen and elastin - thinning and weakening the fibrous cap
3. Mechanical vulnerability: Thin fibrous caps and sites of low shear stress (vessel bifurcations) have reduced nitric oxide and prostacyclin production, more lipid/inflammatory cell accumulation, and greater cap thinning
4. Systemic inflammation: The widespread nature is evidenced by angioscopy showing plaque ulceration at multiple sites simultaneously, and by the higher ACS risk in patients with gingivitis, psoriasis, SLE, and RA
5. Neovascularization: Angiogenic peptides (VEGF, FGF, placental growth factor) promote intraplaque vessel growth, contributing to plaque hemorrhage and destabilization

Thrombus Formation

• Circulating platelets adhere to exposed subendothelial proteins and become activated
• Platelets change from discoid to stellate shape (increasing surface area), then release thromboxane, serotonin, ADP, vWF, and fibrinogen from intracellular granules
• Focal vasoconstriction and recruitment of more platelets follows
• GP IIb/IIIa receptors increase on the platelet surface; fibrinogen bridges adjacent platelets → platelet plug
• Thrombin is generated → activates more platelets and converts fibrinogen to fibrin → fibrin-rich thrombus
• Subtotal occlusion = UA/NSTEMI; total occlusion = STEMI (unless collaterals are present)
• Goldman-Cecil Medicine, p. 640

Special Mechanisms

• Prinzmetal (variant) angina: Focal coronary vasospasm from endothelial dysfunction
• Drug-induced: Cocaine, methamphetamines, chemotherapeutic agents, serotonin receptor agonist "triptans" - increase demand and/or cause vasospasm
• Spontaneous coronary artery dissection (SCAD): Most common in peripartum women and vasculitis patients

Clinical Manifestations

Symptoms

• Classic: retrosternal pressure, squeezing, or heaviness - may radiate to the left arm, neck, or jaw
• May be intermittent/recurrent or persistent
• Accompanying diaphoresis, dyspnea, nausea

Atypical Presentations (especially in elderly and women)

• In patients >85 years, chest pain is present in only ~50% with STEMI
• Older patients and women more often present with: dyspnea, syncope, diaphoresis, shoulder/back pain, abdominal pain, weakness, fatigue, or delirium
• One-third of women >65 years with AMI present with abdominal pain alone
• Delayed presentations with acute heart failure (~50% of STEMI in those >85 years) - Rosen's Emergency Medicine

Diagnosis

ECG (should be interpreted within 10 minutes of arrival)

• STEMI: Persistent ST elevation >20 minutes → prompt reperfusion
• NSTE-ACS: ST depression or transient ST elevation + T wave changes in up to 50%
• A normal ECG does not exclude ACS - ~5% of ACS patients discharged from the ED have a normal initial ECG
• Left circumflex territory ischemia may be missed on standard 12-lead; use posterior leads V7-V9 or right-sided leads
• Deep (>2 mm) symmetrical anterior T-wave inversion suggests significant left main or proximal LAD stenosis
• Serial ECGs at 15-30 minute intervals during the first hour

Serum Biomarkers

• High-sensitivity troponin (hs-cTn) is the gold standard - can detect myonecrosis within 2 hours of symptom onset
• The 0h/1h algorithm (ESC 2020) uses the absolute value at 0h and the change (Δ) at 1 hour to rapidly rule in or rule out NSTEMI

NSTE-ACS Triage Algorithm (ESC 2020)

• Rule-out: hs-cTn very low at 0h, OR low at 0h with no significant 1h rise → discharge with optional stress test/CCTA
• Observe: Intermediate values → repeat at 3h + echocardiography → ECG-monitored bed
• Rule-in: High hs-cTn at 0h OR significant 1h rise → CCU admission + angiography + echocardiography

Coronary Angiography Findings in NSTE-ACS

• Left main disease: ~15%
• 3-vessel disease: 30-35%
• 2-vessel disease: 20-30%
• 1-vessel disease: 20-30%
• No significant stenosis: ~15% (consider INOCA, vasospasm, SCAD)
• Key: 2/3 of culprit lesions had <50% stenosis on prior imaging - previously "non-significant"

Risk Stratification

Management

General Initial Measures

• Continuous ECG monitoring, IV access, oxygen only if SpO₂ <90%
• Aspirin 162-325 mg chewed immediately
• Sublingual nitroglycerin for ongoing chest pain (avoid if hypotension or right ventricular MI)
• Morphine for refractory pain (use cautiously - can mask symptoms and delay P2Y12 absorption)

Antithrombotic Therapy

• Aspirin (irreversibly inhibits COX-1/thromboxane A2): loading 162-325 mg, then 75-100 mg daily
• P2Y12 inhibitors (block ADP-mediated platelet activation via GP IIb/IIIa):
  • Clopidogrel (prodrug, requires CYP2C19 activation) - 300-600 mg load, 75 mg daily
  • Ticagrelor (reversible, faster onset) - 180 mg load, 90 mg twice daily (preferred in most guidelines)
  • Prasugrel (irreversible, potent) - 60 mg load, 10 mg daily; avoid in prior stroke/TIA or age >75

• Unfractionated heparin (UFH): weight-based IV infusion; preferred when PCI likely (reversible with protamine)
• Low-molecular-weight heparin (enoxaparin): 1 mg/kg SC twice daily; non-inferior to UFH in most settings
• Fondaparinux: 2.5 mg SC daily; preferred when PCI not planned (lower bleeding risk)
• Bivalirudin: direct thrombin inhibitor; used as alternative during PCI

Invasive vs. Conservative Strategy

• Early invasive approach (angiography within 24-72h) is recommended for high-risk NSTE-ACS (elevated troponin, dynamic ECG changes, GRACE score >140, refractory symptoms, hemodynamic instability)
• Conservative approach: acceptable for low-risk patients without recurrent symptoms
• AHA guidelines specify no absolute age limit for revascularization - elderly patients, including octogenarians, benefit from early invasive strategy (After Eighty Study)
• Revascularization options: PCI (preferred for single or double vessel disease) or CABG (preferred for left main, triple vessel disease, or diabetes)

Medical Therapy

STEMI-Specific: Reperfusion

• Primary PCI is the preferred reperfusion strategy if door-to-balloon time can be achieved within 90 minutes (or 120 min if transfer required)
• Fibrinolysis (tenecteplase, alteplase, streptokinase): if PCI is unavailable within 120 minutes; administer within 12h of symptom onset
• Absolute contraindications to fibrinolysis: prior hemorrhagic stroke, ischemic stroke within 3 months, intracranial neoplasm, active internal bleeding, suspected aortic dissection

Complications

Secondary Prevention

• DAPT for 12 months post-ACS (then aspirin alone long-term)
• High-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) - target LDL <55 mg/dL per ESC or <70 mg/dL per ACC/AHA
• Beta-blocker: continue for at least 1 year; debate ongoing for patients with preserved EF (a recent 2025 meta-analysis suggests uncertain benefit in post-MI patients without reduced EF or HF)
• ACE inhibitor/ARB indefinitely if EF reduced
• Lifestyle: smoking cessation, cardiac rehabilitation, diet, exercise
• A 2025 Lancet meta-analysis (PMID 40902613) found that clopidogrel was non-inferior to aspirin for secondary prevention of coronary artery disease in individual patient data analysis - suggesting aspirin's role as the default long-term agent may be revisited