Chest Pain — Differential Diagnosis and Approach

Ischemic Heart Disease Mechanisms

• Coronary blood flow insufficiency: Fixed atherosclerotic lesions or dynamic vasospasm reduce oxygen delivery to myocardium below metabolic demands, triggering anaerobic metabolism and accumulation of lactate and hydrogen ions that stimulate cardiac nociceptors via purinergic (P2X) receptors
• Supply-demand mismatch: Increased myocardial oxygen consumption (tachycardia, hypertension, increased contractility) exceeds supply capacity even without obstructive stenosis, as occurs in coronary microvascular dysfunction and demand ischemia (Type 2 myocardial infarction)
• Plaque rupture and thrombosis: Erosion of atherosclerotic plaque exposes tissue factor and collagen to circulating blood, activating coagulation cascade (Factor VII → Factor Xa → thrombin) and platelet aggregation via P2Y12 and thrombin receptors, producing acute coronary occlusion

Aortic Dissection Mechanisms

• Medial layer shearing: Hypertension-induced wall stress exceeds tensile strength of tunica media, initiating intimal tear and dissection plane propagation along elastic lamellae; cystic medial necrosis (marfan syndrome, ehlers-danlos, bicuspid aortic valve) predisposes by weakening structural integrity
• Pain generation: Stimulation of nociceptors in aortic wall and pericardium via unmyelinated C-fibers produces sudden, maximal-intensity "tearing" pain; propagating dissection flap continuously traumatizes nerve endings

Pulmonary Embolism Mechanisms

• Infarction and inflammation: Wedge-shaped peripheral emboli occlude small pulmonary arteries, causing distal hemorrhagic infarction with pleural inflammation and pleuritic pain; centrally located clots produce chest wall pain via transmission of pressure changes
• Right ventricular strain: Acute afterload elevation increases RV wall tension and myocardial oxygen demand, potentially causing RV ischemia and pain; increased RV pressure stretches pericardium

Pleuritic Pain Mechanisms

• Parietal pleural innervation: Parietal pleura receives rich innervation from intercostal and phrenic nerves (C3-C5, thoracic 1-11), whereas visceral pleura is innervated by autonomic fibers; inflammation triggers local prostaglandin production and direct nociceptor stimulation
• Referred pain patterns: Phrenic nerve involvement projects pain to ipsilateral shoulder; lower lobe pleuritis refers to upper abdomen

Musculoskeletal Pain Mechanisms

• Costochondral inflammation: Repetitive trauma or postural strain causes microtrauma and inflammatory cytokine release (IL-6, TNF-α, IL-1β) at costochondral junctions, triggering localized nociceptor activation
• Muscle strain: Direct myofascial injury initiates inflammatory cascade with recruitment of neutrophils and macrophages; sustained muscle contraction produces lactic acidosis and adenosine release, potentiating pain sensation

Esophageal Pain Mechanisms

• Esophageal spasm: Uncoordinated circular and longitudinal muscle contraction (abnormal acetylcholine sensitivity or reduced nitric oxide) generates high-amplitude contractions that distend the esophageal wall and stimulate mucosal nociceptors
• Acid reflux: Gastric acid diffuses across damaged mucosa and activates TRPV1 (vanilloid) receptors on esophageal afferent nerves, producing burning sensation; acid also stimulates vagal afferents

Cardiovascular Causes (Must Not Miss)

• Acute coronary syndrome: ST-elevation myocardial infarction (STEMI), non-ST-elevation MI (NSTEMI), and unstable angina; risk factors include age >40 (men) or >50 (women), smoking, hypertension, dyslipidemia, diabetes mellitus, family history of premature CAD, obesity, chronic kidney disease, inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus), cocaine use, oral contraceptive use (women)
• Aortic dissection: Hypertension (90% of cases), connective tissue disorders (marfan syndrome, ehlers-danlos syndrome type IV), bicuspid aortic valve, coarctation of the aorta, pregnancy (especially third trimester and peripartum period), cocaine use, iatrogenic (cardiac catheterization, cardiac surgery), trauma, Turner syndrome; Type A dissection involves ascending aorta (40% mortality if untreated within 24 hours), Type B involves descending aorta distal to left subclavian artery
• Pulmonary embolism: Virchow's triad components—immobility (recent surgery, prolonged bed rest, long flights), thrombophilia (Factor V Leiden, prothrombin G20210A, protein C/S deficiency, antithrombin III deficiency, antiphospholipid syndrome), and endothelial injury (trauma, indwelling catheters); additional risk factors include malignancy, heart failure, chronic obstructive pulmonary disease, recent myocardial infarction, pregnancy and postpartum period (up to 6 weeks), oral contraceptives and hormone replacement therapy
• Myocarditis/pericarditis: Viral (enterovirus, parvovirus B19, adenovirus, cytomegalovirus, COVID-19), bacterial (streptococcus, staphylococcus aureus), autoimmune (systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis), medications (chemotherapy agents, clozapine, checkpoint inhibitors), radiation, post-myocardial infarction (Dressler syndrome)
• Spontaneous coronary artery dissection (SCAD): Spontaneous intimal tear without atherosclerosis; associated with pregnancy/postpartum period, fibromuscular dysplasia, connective tissue disorders, emotional stress, extreme exertion; predominantly affects women and younger patients

Pulmonary Causes

• Pneumothorax: Primary (spontaneous, typically in tall thin men with blebs) or secondary to underlying lung disease (COPD, cystic fibrosis, lymphangioleiomyomatosis, idiopathic pulmonary fibrosis); tension pneumothorax is life-threatening
• Pulmonary hypertension: Chronic thromboembolic disease, idiopathic pulmonary arterial hypertension, left heart disease, lung disease, connective tissue disease; causes RV strain and dyspnea-related chest discomfort
• Acute respiratory infections: Pneumonia, bronchitis, viral upper respiratory infections with associated pleuritis

Gastrointestinal Causes

• Gastroesophageal reflux disease (GERD): Chronic reflux, typically postprandial or recumbent; may be indistinguishable from cardiac pain
• Esophageal spasm: Diffuse or segmental uncoordinated contractions; can mimic angina
• Peptic ulcer disease/gastritis: Burning epigastric pain, often relieved by antacids
• Esophageal rupture (Boerhaave syndrome): Spontaneous rupture following forceful vomiting or straining; medical emergency with high mortality

Musculoskeletal Causes

• Costochondritis: Inflammation of costochondral junctions; reproducible with palpation
• Muscle strain/trauma: History of strenuous activity, cough, or direct injury
• Rib fractures: Traumatic injury, pathological fractures (multiple myeloma, metastatic disease, osteoporosis)
• Fibromyalgia: Widespread musculoskeletal pain with tender points

Neurological Causes

• Herpes zoster (shingles): Dermatomal distribution, prodromal paresthesias, vesicular rash
• Thoracic radiculopathy: Root compression from spondylosis, disc herniation, or foraminal stenosis

Psychiatric Causes

• Panic disorder/anxiety: Often accompanied by hyperventilation, palpitations, diaphoresis; diagnosis of exclusion
• Somatization disorder: Multiple somatic complaints without clear organic pathology

Cardinal Symptom Characteristics

• Quality of pain: Pressure/heaviness (ACS), tearing/ripping (dissection), sharp/stabbing (pleuritis/pericarditis), burning (GERD/esophageal spasm), aching (musculoskeletal)

• Onset and duration: Abrupt maximal intensity suggests dissection or PE; gradual worsening suggests ACS; intermittent suggests musculoskeletal or esophageal causes

• Location: Retrosternal (ACS, GERD, esophageal spasm), left-sided anterior chest (pericarditis, musculoskeletal), back (dissection), pleuritic pain at site of infarction/inflammation, shoulder (referred from phrenic nerve or diaphragmatic involvement)

• Radiation patterns: Radiation to left arm, jaw, or neck (ACS); to back between scapulae (dissection); to shoulder (phrenic involvement in PE or pericarditis)

• Provocation/palliation: Exertional onset relieved by rest (stable angina); not relieved by rest (ACS, dissection); positional or pleuritic worsening (pericarditis, pleuritis); reproducible with palpation (musculoskeletal); postprandial or recumbent (GERD)

• Associated symptoms: Diaphoresis, dyspnea, nausea/vomiting, palpitations (ACS/PE); neurological deficits, syncope (dissection with branch involvement); hemoptysis (massive PE); focal pleurisy with friction rub (pleuritis); fever (infection/inflammation)

Physical Examination Findings

• Vital signs abnormalities: Hypotension (cardiogenic shock, massive PE, tension pneumothorax, sepsis); hypertension (aortic dissection, anxiety, ACS); tachycardia (PE, hemorrhagic shock, anxiety, hyperthyroidism); tachypnea (PE, pneumonia, pneumothorax, heart failure); oxygen desaturation (PE, pneumonia, pneumothorax)

• Cardiovascular exam: New murmur (acute mitral regurgitation from papillary muscle rupture or endocarditis); pulse deficits or blood pressure differential between arms (dissection involving branch vessels or descending aorta); signs of heart failure (S3 gallop, pulmonary crackles, elevated JVP, lower extremity edema); friction rub (pericarditis); muffled heart sounds (pericardial effusion/tamponade)

• Pulmonary exam: Decreased breath sounds and hyperresonance (pneumothorax); crackles (pneumonia, pulmonary edema); pleural friction rub (pleuritis); unilateral decreased breath sounds with hemodynamic instability (tension pneumothorax)

• Extremity exam: Unilateral calf swelling, warmth, erythema (DVT suggesting PE source); unequal pulses

• Chest wall exam: Reproducible tenderness with palpation at costochondral junctions (costochondritis); muscle tenderness and trigger points (myofascial pain); dermatomal vesicular rash (herpes zoster)

• Other findings: Diaphoresis (ACS, acute dissection, PE), pallor (shock states), cyanosis (severe hypoxemia), focal neurological deficits (dissection with branch involvement), signs of sepsis (fever, erythema, petechiae in endocarditis)

Clinical Risk Stratification Frameworks

• HEART Score (for ACS in chest pain patients): History (0-2 points: high-risk features), ECG (0-2 points: ischemic changes), Age (0-2 points: ≥65 years), Risk factors (0-2 points: hypertension, diabetes, smoking, cholesterol, family history), Troponin (0-2 points: elevated). Scores 0-3 (2.4% 6-week MACE risk) = low risk; 4-6 = intermediate risk; ≥7 = high risk; facilitates risk stratification and disposition

• Wells Pulmonary Embolism Rule: Clinical probability assessment: >50% (high), 20-50% (intermediate), <20% (low) based on clinical suspicion, leg swelling/pain, heart rate >100, respiratory rate >20, temperature <36.5°C, hemoptysis, signs of DVT, right heart strain on echo/ECG. Guides D-dimer and imaging thresholds

• Aortic Dissection Risk Score (ADD-RS): Presence of any one of: high risk features present (sudden onset maximal intensity pain, tearing quality, blood pressure >160/100 or pulse deficit), risk conditions (Marfan, bicuspid aortic valve, aortic surgery, cocaine, hypertension), and imaging findings

Electrocardiography (12-lead ECG)

• Acute ST-segment elevation myocardial infarction (STEMI): ≥1 mm ST elevation in contiguous leads (or ≥2 mm in precordial leads V1-V3); reciprocal ST depression; pathognomonic finding requiring emergent reperfusion therapy (primary PCI or thrombolytics). Anterior STEMI (LAD territory) shows changes in V1-V4; inferior STEMI (RCA or LCx) in II, III, aVF; posterior STEMI (tall R waves in V1-V2); right ventricular involvement indicated by ST elevation in V4R

• Non-ST-elevation myocardial infarction (NSTEMI): ST depression ≥0.5 mm and/or T-wave inversions in multiple contiguous leads reflecting subendocardial ischemia; troponin elevation confirms diagnosis

• Unstable angina: ECG may show T-wave inversions, ST depression, or be normal; distinguished from NSTEMI by absence of troponin elevation

• Wellens sign: Specific pattern indicating critical LAD stenosis—symmetric T-wave inversions in V2-V3 with minimal ST elevation; high risk for anterior STEMI and indicates need for urgent revascularization

• De Winter T waves: Symmetric T-wave inversions in V1-V6 with upsloping ST segment in V1-V4 (resembles Wellens) indicating acute STEMI equivalent

• Pericarditis: Diffuse concave ST elevation (except aVR, V1 which show ST depression); PR segment depression (more specific for pericarditis than ST elevation); evolving pattern with normalization and T-wave inversions

• Pulmonary embolism: Classic findings (present in <25% of cases)—sinus tachycardia, S1Q3T3 pattern (S wave in I, Q wave and T-wave inversion in III), atrial fibrillation, right axis deviation; more commonly shows nonspecific ST-T changes

• Aortic dissection: Nonspecific changes; may show normal ECG despite severe pathology; inferior STEMI pattern may occur if dissection involves RCA

• Pneumothorax: May show electrical alternans (beat-to-beat variation in QRS amplitude from swinging heart); usually nonspecific or normal

Cardiac Biomarkers

• High-sensitivity troponin I and T: Superior sensitivity and negative predictive value compared to conventional troponin; enables single negative troponin at presentation plus clinical assessment to rule out ACS in some populations; rise and fall pattern essential for diagnosis (elevation indicates myocardial necrosis from any cause—ACS, myocarditis, PE, sepsis, heart failure, renal failure

Immediate stabilisation (all undifferentiated chest pain)

• Monitored bed, IV access, pulse oximetry, 12-lead ECG within 10 minutes of arrival: the 2021 AHA/ACC Chest Pain Guideline makes early ECG the pivot point, because reperfusion decisions are time-dependent and cannot wait for troponin.
• Oxygen only for saturation <90%: supplemental O₂ in normoxaemic ACS causes coronary vasoconstriction and offers no mortality benefit.
• Aspirin, chewed (162–325 mg): irreversible COX-1/thromboxane A₂ blockade limits platelet aggregation on the ruptured plaque — give once ACS is plausible and dissection is not strongly suspected.

Condition-directed first-line therapy

• STEMI: emergent reperfusion per ACC/AHA — primary PCI is preferred, with fibrinolysis (e.g., tenecteplase) reserved for centres unable to achieve timely PCI transfer. Add a P2Y12 inhibitor (ticagrelor), parenteral anticoagulation (unfractionated heparin), high-intensity statin (atorvastatin 80 mg), and a beta blocker within 24 hours if no shock or heart block.
• NSTEMI/unstable angina: anti-ischaemic and antithrombotic therapy with risk-stratified invasive angiography; high-risk features (refractory ischaemia, instability, arrhythmia) prompt an early invasive strategy.
• Aortic dissection: per the 2022 ACC/AHA Aortic Disease Guideline, IV beta blockade first (esmolol or labetalol) to lower dP/dt and heart rate, then a vasodilator (nitroprusside) — reversing this order provokes reflex tachycardia and extends the dissection. Type A dissection is an emergency open surgical repair; complicated type B → TEVAR.
• Pulmonary embolism: anticoagulation (LMWH or a DOAC such as apixaban) per CHEST antithrombotic guidance; systemic thrombolysis for haemodynamic instability, with catheter-directed therapy or embolectomy as escalation.
• Tension pneumothorax: needle decompression before imaging, followed by tube thoracostomy.
• Pericarditis: NSAID plus colchicine; GERD: proton pump inhibitor; costochondritis: NSAID and reassurance.

Contraindicated

• Nitrates with recent PDE5 inhibitor use, in RV infarction, or severe aortic stenosis (preload-dependent hypotension).
• Fibrinolytics or antiplatelets when dissection is suspected — catastrophic haemorrhage.
• Unopposed beta blockade in cocaine-associated chest pain (benzodiazepines preferred).
• Corticosteroids as first-line pericarditis therapy — higher recurrence rates.

Complications of acute coronary syndrome (mechanism → signal)

• Ventricular fibrillation / pulseless VT: reentry around ischaemic myocardium; the shockable pair — immediate defibrillation. Emergency.
• Cardiogenic shock: loss of contractile mass >40% of LV; hypotension with cool extremities, rising lactate, oliguria. Emergency.
• Papillary muscle rupture: posteromedial papillary muscle has single-vessel supply, so inferior MI predisposes; new holosystolic murmur with flash pulmonary oedema days after MI. Emergency — surgical.
• Interventricular septal rupture: harsh murmur with thrill and left-to-right shunt physiology. Emergency.
• Free wall rupture / tamponade: sudden pulseless electrical activity, distended neck veins. Emergency.
• AV block and bradyarrhythmia: AV nodal artery arises from the RCA — inferior MI produces high-grade block, often atropine-responsive.
• LV aneurysm with mural thrombus: persistent ST elevation weeks later plus embolic stroke.

Complications of the other emergencies

• Aortic dissection: retrograde extension causes acute aortic regurgitation, coronary ostial occlusion (inferior MI pattern), haemopericardium with tamponade, or branch malperfusion (stroke, limb ischaemia, mesenteric ischaemia, anuria). All emergencies.
• Pulmonary embolism: acute RV pressure overload → RV failure and obstructive shock (hypotension with elevated JVP, clear lungs); chronic residual obstruction → CTEPH with progressive dyspnoea.
• Boerhaave syndrome: mediastinitis and septic shock; subcutaneous emphysema and pneumomediastinum. Emergency.

Complications of treatment

• Fibrinolysis: intracranial haemorrhage — new headache or focal deficit mandates stopping the drug and emergent CT.
• Dual antiplatelet/anticoagulant therapy: GI and access-site bleeding; heparin-induced thrombocytopenia with paradoxical thrombosis and falling platelets.
• Premature DAPT discontinuation after stenting: stent thrombosis presenting as recurrent STEMI. Emergency.
• PCI: contrast-associated acute kidney injury, coronary dissection, cholesterol embolisation.
• Nitroprusside: cyanide/thiocyanate toxicity with prolonged high-dose infusion — altered mental status and lactic acidosis.
• Nitrates/beta blockers: hypotension, especially in RV infarction or unrecognised shock.

• The single best next step in undifferentiated acute chest pain is a 12-lead ECG within 10 minutes, before troponin, imaging, or analgesia — the 2021 AHA/ACC Chest Pain Guideline builds the entire pathway on it.
• The shockable rhythm pair is ventricular fibrillation and pulseless ventricular tachycardia — defibrillate immediately; asystole and PEA are not shockable.
• In suspected aortic dissection, beta blocker precedes vasodilator. Giving nitroprusside first causes reflex tachycardia and increased dP/dt. Blood pressure differential between arms, pulse deficit, or widened mediastinum → CT angiography of the aorta (TEE if too unstable to travel or renal failure precludes contrast).
• Never give fibrinolytics, heparin, or a P2Y12 inhibitor to a patient whose "inferior STEMI" is actually a type A dissection occluding the RCA ostium — this is the classic examiner trap in a hypertensive patient with tearing interscapular pain.
• Nitroglycerin relief does not confirm cardiac ischaemia, and reproducible chest wall tenderness does not exclude ACS — both are favourite distractors. Likewise, a normal ECG does not exclude NSTEMI.
• A young peripartum or postpartum woman with MI and no atherosclerotic risk factors: think spontaneous coronary artery dissection (SCAD), often managed conservatively rather than with routine stenting; look for associated fibromuscular dysplasia.
• Cocaine-associated chest pain: benzodiazepines plus nitrates; avoid unopposed beta blockade because of the theoretical risk of alpha-mediated coronary vasoconstriction.
• PR-segment depression is more specific for pericarditis than diffuse ST elevation, and pericarditis is treated with NSAID plus colchicine, not anticoagulation — anticoagulating a patient with pericarditis risks haemorrhagic effusion.
• Troponin marks myocardial necrosis, not coronary thrombosis: PE, myocarditis, sepsis, heart failure, and chronic kidney disease all elevate it. A rise-and-fall pattern with ischaemic symptoms is what makes it ACS.
• D-dimer is only useful when pretest probability for PE is low or intermediate; ordering it in a high-probability patient wastes time — go straight to CT pulmonary angiography.