Vasospastic Angina — Prinzmetal Angina

Coronary Vasospasm Mechanisms

• Endothelial dysfunction with reduced production and bioavailability of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF); decreased NO availability results from either reduced endothelial NO synthase (eNOS) expression or increased oxidative stress via reactive oxygen species (ROS) production, which rapidly inactivates NO to form peroxynitrite
• Enhanced vascular smooth muscle reactivity to vasoconstrictive stimuli via increased sensitivity to endothelin-1 (ET-1), catecholamines, and serotonin (5-HT); hyperresponsiveness may involve increased expression of endothelin receptors (ETA and ETB) and α₁-adrenergic receptors on coronary smooth muscle
• Abnormal calcium handling in coronary smooth muscle cells resulting in increased intracellular calcium concentration and heightened contractile responsiveness to normal or minimal stimuli; this involves dysregulation of voltage-gated calcium channels and ryanodine receptors on the sarcoplasmic reticulum

Trigger Mechanisms

• Autonomic dysfunction with exaggerated parasympathetic (vagal) tone and reduced parasympathetic withdrawal during sleep, accounting for the characteristic nocturnal and early morning clustering of episodes
• Inflammatory activation with infiltration of mast cells and T lymphocytes in coronary vessel walls, leading to local release of inflammatory mediators (histamine, tryptase, cytokines) that promote vasoconstriction
• Hyperventilation, emotional stress, exposure to cold, cocaine use, and ergot alkaloids serving as recognized precipitants that unmask underlying vasomotor instability

Electrophysiologic Consequences

• Transient myocardial ischemia during vasoconstriction periods leads to localized ST-segment elevation on electrocardiography (ECG) corresponding to the affected coronary territory; severe or prolonged ischemia may precipitate J waves (Osborn waves) and peaked T waves
• Ischemia-induced electrolyte abnormalities (particularly increased extracellular potassium and altered intracellular calcium) create a proarrhythmic substrate predisposing to ventricular fibrillation and polymorphic ventricular tachycardia, explaining the risk of sudden death despite absence of extensive myocardial necrosis

Primary (Idiopathic) Vasospastic Angina

• Constitutes approximately 60–80% of vasospastic angina cases with no identifiable underlying cause; likely represents a final common pathway of multiple genetic and environmental factors affecting endothelial function and vascular reactivity

Secondary Vasospastic Angina

• Atherosclerotic coronary artery disease with spasm occurring at sites of minimal or moderate fixed stenosis (30–70% diameter reduction); plaque-associated endothelial injury and local inflammatory changes predispose to vasoreactivity
• Substance-induced vasospasm: cocaine (blocks catecholamine reuptake leading to excessive sympathomimetic stimulation), amphetamines, ergot alkaloids (ergotamine, bromocriptine), and 5-fluorouracil (chemotherapy agent)
• Coronary artery anomalies (anomalous left main coronary origin from right sinus of Valsalva, single coronary artery)
• Inflammatory/autoimmune disorders: systemic lupus erythematosus (SLE), polyarteritis nodosa, Raynaud phenomenon, scleroderma

Risk Factors & Associated Conditions

• Smoking (even passive exposure increases vasospasm risk 2–3-fold; mechanisms include endothelial dysfunction and increased sympathetic tone)
• Hypertension and diabetes mellitus (both associate with endothelial dysfunction and increased oxidative stress)
• Dyslipidemia (elevated LDL promotes oxidative stress and NO depletion)
• Migraine headaches and Raynaud phenomenon (suggesting shared vasomotor instability)
• Genetic predisposition with familial clustering reported; polymorphisms in endothelial NO synthase (eNOS) gene and other vasomotor regulatory genes identified
• Hormone replacement therapy and oral contraceptives (estrogen-related changes in endothelial function)
• Sleep apnea with repetitive hypoxic episodes triggering sympathetic activation and endothelial dysfunction
• Anxiety and depression (associated with autonomic dysregulation)

Cardinal Symptoms

• Rest angina (most characteristic): Anginal chest discomfort occurring predominantly during sleep or upon awakening, often between midnight and 8 AM; episodes typically last 5–30 minutes and resolve spontaneously or rapidly with sublingual nitroglycerin (NTG)
• Severe, crushing substernal chest pain described as pressure, heaviness, or squeezing sensation; radiation to left shoulder, arm, jaw, or back may occur
• Associated autonomic symptoms: Diaphoresis, dyspnea, nausea, palpitations, and sensation of impending doom during episodes; in contrast to exertional angina, symptoms often occur at rest without precipitating factors
• Absence of dyspnea on exertion or anginal equivalent symptoms (fatigue, jaw claudication) during normal daily activities; exercise tolerance typically well-preserved unless atherosclerotic disease coexists

Physical Examination Findings

• Normal baseline examination between episodes; no specific physical findings
• Transient findings during acute vasospasm episode: Tachycardia, hypertension, diaphoresis, pallor; occasionally new gallop rhythm (S3 or S4 gallop) reflecting acute left ventricular dysfunction from regional ischemia
• Signs of autonomic instability: Tremor, anxiety, variable vital signs
• Absence of murmurs, rubs, or peripheral edema in uncomplicated cases (unless atherosclerotic disease or heart failure coexists)

Clinical Diagnostic Approach

Electrocardiography (ECG) Findings

• During symptomatic episodes: ST-segment elevation (typically 1–5 mm) in one or more contiguous leads corresponding to the territory of the affected coronary artery; ST elevation in inferior leads (II, III, aVF) suggests right coronary artery (RCA) spasm (60% of cases), while anterior ST elevation (V1–V4) indicates left anterior descending (LAD) spasm; left circumflex (LCx) spasm produces lateral ST elevation (I, aVL, V5–V6)
• Accompanying ECG changes: Peaked T waves, T wave inversion upon resolution of ST elevation, U waves, arrhythmias (premature ventricular contractions, ventricular tachycardia, bradycardia from vagal tone)
• Between episodes: Baseline ECG typically entirely normal or shows only nonspecific repolarization changes; this normality between attacks is a distinguishing feature

Stress Testing (Limited Utility)

• Exercise stress testing: Often normal or negative because vasospasm is typically triggered at rest and not provoked by exertion; low sensitivity (60%) and limited diagnostic value compared to other presentations of angina
• Hyperventilation testing: Historically used to provoke vasospasm (mechanism unclear but possibly involves respiratory alkalosis and CO₂ depletion); rarely performed currently due to low sensitivity and specificity

Provocative Testing

• Ergonovine provocation test (ergot alkaloid acts as direct smooth muscle vasoconstrictor; primarily ETA and ETB endothelin receptor agonism): Administered intravenously or intracoronary during angiography; reproduces ST-segment elevation, anginal symptoms, and angiographic coronary constriction (>70% diameter reduction); highly specific (95%) but sensitivity variable (60–90% depending on study population and testing conditions); risk of life-threatening arrhythmias during testing requires continuous monitoring and immediate access to intracoronary NTG for reversal
• Intracoronary acetylcholine testing: Acetylcholine (an endothelium-dependent vasodilator in normal vessels but causes paradoxical vasoconstriction in dysfunctional endothelium) injected directly into coronary tree during angiography; positive response is exaggerated vasoconstriction (≥70% diameter reduction) reproducing symptoms and ST changes; excellent specificity but less widely performed than ergonovine
• Adenosine-induced spasm (less commonly used): Adenosine's role in vasospasm remains debated

Coronary Angiography (Gold Standard)

• Appearance during spasm: Severe, dynamic, focal coronary artery narrowing (often near total occlusion) occurring spontaneously or after provocative agent administration; the "string sign" describes a thread-like appearance of severely constricted vessel
• Appearance between spasm episodes: Minimal or absent atherosclerotic lesions (normal or near-normal coronary arteries); when disease is present, typically mild (10–50% diameter stenosis); this contrasts with typical atherosclerotic angina
• Location of spasm: Right coronary artery (60%) > left anterior descending (25%) > left circumflex (15%); multivessel spasm occurs in 10–15% of patients
• Response to intracoronary NTG: Rapid reversal of spasm with restoration of normal coronary diameter and vessel appearance confirms vasospastic etiology

Laboratory and Imaging Studies

• Troponin and myoglobin: Elevated only if infarction has occurred; usually normal in uncomplicated vasospastic angina despite symptoms
• BNP/NT-proBNP: Normal in absence of heart failure
• Echocardiography: Normal baseline with preserved left ventricular ejection fraction (LVEF ≥50%); may show transient wall motion abnormality during or shortly after ischemic episode corresponding to vascular territory of spasm, but this is rarely captured on imaging; useful to exclude other causes of symptoms
• Cardiac MRI: May demonstrate absence of scar or minimal subendocardial scar even after repeated ischemic episodes, supporting vasospastic etiology
• Chest radiograph: Normal in uncomplicated cases

Diagnostic Criteria (Modified from Various Guidelines)

1. 1.Typical chest pain at rest (particularly nocturnal/early morning)
2. 2.ST-segment elevation (≥1 mm) on ECG during symptomatic episodes with resolution upon symptom relief
3. 3.Rapid response to sublingual or intravenous NTG
4. 4.Normal or minimal coronary atherosclerosis on angiography
5. 5.Positive response to provocative testing (ergonovine or acetylcholine) demonstrating coronary vasoconstriction with symptom and ECG reproduction (optional but confirmatory if diagnosis unclear)

First-Line Pharmacotherapy

• Long-acting calcium channel blockers (CCBs) — Mechanism: Direct smooth muscle relaxation via inhibition of L-type voltage-gated calcium channels; prevention of calcium influx reduces excitation-contraction coupling and vascular smooth muscle contraction
• Dihydropyridines (e.g., extended-release nifedipine 30–90 mg daily, amlodipine 5–10 mg daily, diltiazem 120–360 mg daily in divided doses): Preferred for vasospastic angina; provide peripheral vasodilation with coronary vasodilation and reduce vasospasm frequency by 80–90%
• Non-dihydropyridines (verapamil 120–360 mg daily, diltiazem 120–360 mg daily): Provide additional benefits of AV nodal slowing and negative inotropic effects; verapamil particularly effective for vasospastic angina
• Dosing: Titrate to symptom control and tolerance; combination therapy with both dihydropyridines and non-dihydropyridines sometimes employed for refractory cases
• Expected response: Reduction or elimination of vasospastic episodes in majority of patients within days to weeks

• Long-acting nitrates — Mechanism: Exogenous NO donation via denitration to produce guanylate cyclase activation, increasing cGMP and causing smooth muscle relaxation; direct anti-ischemic and anti-vasospasm effects
• Isosorbide mononitrate (30–60 mg daily) or isosorbide dinitrate (10–40 mg two to three times daily with 10–14 hour nitrate-free interval to prevent tolerance)
• Role: Adjunctive to CCBs for refractory symptoms; less effective as monotherapy compared to CCBs
• Nitrate tolerance: Requires 10–14 hour daily nitrate-free interval to maintain efficacy

Second-Line Therapy

• Beta-blockers: Contraindicated as monotherapy (unopposed alpha-adrenergic stimulation may worsen vasospasm); however, can be used adjunctively with concurrent CCB/nitrate therapy in patients with coexisting atherosclerotic disease or arrhythmias; non-selective beta-blockers preferable to beta-1-selective agents if used
• Alpha-2 adrenergic antagonists (e.g., prazosin): Limited evidence; may reduce vasospasm in selected patients through alpha-1 blockade; less commonly used
• ACE inhibitors or angiotensin II receptor blockers: Modest benefit through improved endothelial function and reduction of local angiotensin II-mediated vasoconstriction; useful if hypertension or atherosclerotic disease coexists
• Statin therapy (e.g., atorvastatin 40–80 mg daily): Improves endothelial function through NO-mediated mechanisms and reduces systemic inflammation; considered in all patients, particularly if dyslipidemia or atherosclerotic disease present
• Aspirin (81–325 mg daily): Limited direct effect on vasospasm but recommended for secondary prevention in patients with atherosclerotic disease or history of infarction
• Phosphodiesterase-5 inhibitors (e.g., sildenafil): Experimental evidence suggests benefit through cGMP potentiation and smooth muscle relaxation; not standard therapy but investigated for refractory cases

Acute Episode Management

• Sublingual nitroglycerin (NTG) (0.3–0.6 mg): Immediate vasodilation with symptom relief typically within 5–10 minutes; if symptoms persist after 5 minutes, repeat dose every 5 minutes (up to three doses over 15 minutes) and seek emergency evaluation if no relief
• Intravenous or intracoronary NTG during hospitalization for refractory episodes or acute MI

Non-Pharmacological Measures

• Smoking cessation (critical intervention): Smoking directly worsens vasospasm; cessation reduces spasm frequency and recurrent MI risk
• Avoid known precipitants: Exposure to cold, emotional stress, hyperventilation, cocaine and other sympathomimetic drugs, ergot alkaloids
• **Stress management

Disease-related complications

• Acute myocardial infarction: prolonged or subtotal spasm produces transmural ischemia identical physiologically to thrombotic occlusion; signaled by chest pain that does not resolve with sublingual nitroglycerin plus a rising troponin. Emergency — transient ST elevation cannot be distinguished from true STEMI at the bedside, and the ACC/AHA/SCAI 2021 Chest Pain guideline supports urgent invasive evaluation for ongoing ischemic ST elevation.
• Ventricular fibrillation / pulseless ventricular tachycardia: ischemia-induced dispersion of repolarization creates reentry; signaled by syncope during a pain episode or cardiac arrest, often nocturnal. Emergency — these are the shockable rhythms of ACLS and the mechanism of sudden death in this syndrome.
• High-grade AV block, sinus arrest, or profound bradycardia: RCA spasm compromises the AV nodal and sinus nodal arteries and amplifies vagal tone; signaled by syncope with bradycardia rather than tachyarrhythmia during an episode. Emergency if hemodynamically significant.
• Recurrent ischemia-driven complications: transient regional wall motion abnormality with heart failure symptoms, and rarely ischemic mitral regurgitation with a new murmur; these usually resolve as spasm reverses.
• Refractory/multivessel spasm after abrupt withdrawal of calcium channel blockers or nitrates — rebound episodes cluster and can precipitate arrest.

Treatment-related complications

• Calcium channel blockers: hypotension, flushing, headache, and dependent edema (arteriolar dilation); verapamil and diltiazem add constipation, bradycardia, and AV block, particularly when combined with a beta blocker.
• Nitrates: headache, orthostatic hypotension, and tolerance without a nitrate-free interval; catastrophic hypotension if combined with a PDE-5 inhibitor — an absolute contraindication.
• Beta blockers as monotherapy: may prolong or intensify spasm; the clue is worsening rest angina after starting the drug.
• Provocative testing (ergonovine, acetylcholine): can induce refractory spasm, arrhythmia, or infarction; performed only with intracoronary nitroglycerin and defibrillation immediately available.

• The stem's fingerprint: a relatively young smoker with chest pain at rest, between midnight and early morning, transient ST-segment elevation that resolves completely — symptoms and ECG — after sublingual nitroglycerin, with normal or near-normal coronary arteries on angiography and normal troponin.
• Single best next step during pain: a 12-lead ECG obtained while the patient is symptomatic — the tracing normalizes between attacks, so a normal interval ECG never excludes the diagnosis. Ambulatory ECG monitoring is the way to capture episodes when the diagnosis is suspected but unproven.
• Best next step in management: a long-acting calcium channel blocker (dihydropyridine such as amlodipine, or diltiazem/verapamil) is the mainstay; the 2023 AHA/ACC Chronic Coronary Disease guideline supports CCBs with nitrates as adjuncts, plus smoking cessation, which is the highest-yield non-pharmacologic intervention.
• The association examiners test: smoking is the dominant risk factor, while the classic atherosclerotic profile is often absent; look also for the vasospastic cluster of migraine and Raynaud phenomenon in the same patient.
• Cocaine-associated chest pain is the recurring vignette: manage with benzodiazepines plus nitrates/CCB, and follow the AHA scientific statement's caution against beta blockers in the acute cocaine setting.
• Distractor to avoid: choosing a beta blocker — it is not the answer here and may worsen spasm; likewise do not choose PCI/stenting for a vessel with no fixed obstruction, and never pair a nitrate with a PDE-5 inhibitor.
• Distractor to avoid: calling exercise stress testing diagnostic — it is typically negative because spasm is a rest phenomenon. Provocative testing with ergonovine or acetylcholine during angiography is the confirmatory maneuver, not treadmill testing.
• Do not under-triage: ischemic ST elevation is treated as ACS until proven otherwise; per the ACC/AHA/SCAI 2021 Chest Pain guideline, urgent angiography is appropriate, and the diagnosis of spasm is made when the catheterization shows non-obstructive vessels.