Myocardial Infarction Due to Coronary Vasospasm

Myocardial infarction due to coronary vasospasm is myocardial necrosis caused by prolonged focal or diffuse epicardial spasm in the absence of a fixed obstructive lesion, or with a minor underlying plaque. It is a form of myocardial infarction with non-obstructive coronary arteries and an extreme expression of vasospastic (variant) angina.

Vasospastic angina is commonest in East Asian populations and in younger women and men who smoke. Spasm is found in about 1 to 2% of patients undergoing angiography in Western countries, more in Japan, and it is the cause in about 3% of infarcts with non-obstructive arteries and a larger share in selected series.

Triggers are smoking, cocaine, amphetamines and cannabis, 5-fluorouracil and capecitabine, triptans, ergot derivatives, hyperventilation, alcohol withdrawal, cold exposure, emotional stress, magnesium deficiency, thyrotoxicosis, and allergic reactions. Attacks cluster from midnight to early morning.

Arrhythmia is frequent, and ventricular fibrillation, high grade block and sudden death can occur.

Pathophysiology.

Hyperreactivity of coronary smooth muscle (increased Rho kinase activity), endothelial dysfunction with reduced nitric oxide, autonomic imbalance (increased sympathetic and reduced parasympathetic activity at night), oxidative stress and inflammation lead to sudden vasoconstriction.

Complete spasm for 20 minutes or more causes infarction, and repeated spasm and reperfusion cause myocardial stunning and arrhythmia. Non-selective beta blockers and aspirin at high doses may aggravate spasm (unopposed alpha activity, reduced prostacyclin).

Rest chest pain, often at night or early morning, relieved by nitrates, in a patient with few conventional risk factors but with smoking, stimulant or drug exposure. Syncope, palpitations and sudden cardiac arrest occur. Pain may follow exercise in the morning and not later in the day. Examination is often normal between episodes.

• ECG during pain: transient ST elevation (or depression, T-wave pseudonormalisation, arrhythmia) that resolves with nitrates. Continuous ECG or 24 to 48 hour ambulatory monitoring may capture episodes.
• Troponin, which is raised in infarction, and echocardiography (regional wall motion abnormality).
• Coronary angiography: no fixed stenosis (or a minor plaque under 50%), with spasm relieved by intracoronary nitroglycerin 100 to 200 microgram.
• Provocation testing, only when stable and not during acute infarction: intracoronary acetylcholine in incremental doses, left coronary artery 20, 50 and 100 microgram (up to 200 microgram) and right coronary artery 20, 50 and 80 microgram, each over 20 seconds with 3 minutes between doses, with ECG and angiography. A positive test shows focal or diffuse constriction of 90% or more with reproduction of the usual symptoms and ischaemic ECG changes. Reverse with intracoronary nitroglycerin 100 to 200 microgram. Ergonovine testing is an alternative where available.
• Urine toxicology for cocaine and amphetamine, thyroid function, magnesium and calcium.
• Cardiac MRI to exclude myocarditis and Takotsubo syndrome in infarction with non-obstructive arteries.

Differential diagnosis.

• Atherothrombotic infarction and spontaneous coronary artery dissection.
• Takotsubo syndrome, myocarditis and coronary embolism.
• Kounis syndrome and microvascular angina.
• Pericarditis, pulmonary embolism and oesophageal spasm.

Acute spasm and infarction.

• Glyceryl trinitrate 400 to 800 microgram sublingually, repeated every 5 minutes up to 3 doses, then 10 to 200 microgram/min intravenously titrated to pain and blood pressure.
• Intravenous diltiazem 0.25 mg/kg over 2 minutes (then 5 to 15 mg/h infusion), or nicorandil, when pain persists; avoid in hypotension, bradycardia or heart failure.
• Urgent angiography for persistent ST elevation. Intracoronary nitroglycerin 100 to 200 microgram, repeated as needed. Stent only for a fixed residual stenosis of 50% or more after nitrate.
• Avoid non-selective beta blockers and sympathomimetics. In cocaine associated spasm, give benzodiazepine (lorazepam 1 to 2 mg intravenously, repeated) alongside nitrate and calcium channel blocker therapy for the spasm.

Long term prevention.

• Calcium channel blockers are first line: diltiazem sustained release 120 to 360 mg orally once daily (maximum 360 mg), or amlodipine 5 to 10 mg once daily (maximum 10 mg), or verapamil sustained release 240 to 480 mg once daily (maximum 480 mg; check heart rate and PR interval), or nifedipine modified release 30 to 90 mg once daily. Combine a dihydropyridine with diltiazem or verapamil in refractory disease, accepting more hypotension and bradycardia.
• Long acting nitrate (isosorbide mononitrate 30 to 120 mg once daily, with a nitrate free interval) or nicorandil 5 to 20 mg twice daily (mouth ulcers; avoid with phosphodiesterase-5 inhibitors and in hypotension).
• Aspirin 75 to 100 mg daily (high doses avoided), atorvastatin 20 to 40 mg daily, and removal of triggers: stop smoking and stimulants, stop or switch 5-fluorouracil, capecitabine or triptans.
• Beta blockers are avoided, except cardioselective drugs (bisoprolol 2.5 to 10 mg daily) in patients on a calcium channel blocker who need them for arrhythmia or other indications.
• Refractory disease: add cilostazol 50 to 100 mg twice daily (avoid in heart failure), magnesium correction, or Rho kinase inhibitors (fasudil, where available).
• Implantable defibrillator for survivors of ventricular fibrillation or sustained ventricular tachycardia from spasm, particularly when attacks recur despite combination therapy, together with continued vasodilator therapy.
• Continue calcium channel blockers for at least 6 to 12 months after symptoms resolve, then taper gradually while monitoring, since abrupt withdrawal can cause rebound spasm.

Monitoring. Symptoms and nocturnal ECG at 2 to 4 weeks, heart rate, blood pressure and PR interval on diltiazem or verapamil, peripheral oedema on dihydropyridines, ambulatory ECG at 3 months, echocardiography at 1 and 3 months after infarction.

Referral and escalation. Refer all patients with infarction and suspected spasm to cardiology, with provocation testing in a specialist centre. Urgent referral for ventricular arrhythmia, syncope or recurrent pain despite two drugs.

Special groups.

• Pregnancy: calcium channel blockers (nifedipine, amlodipine) are used; avoid ergot derivatives; nicorandil is avoided.
• Chemotherapy with fluoropyrimidines: stop the drug at the first episode, give nitrate and calcium channel blocker, and rechallenge only with specialist advice and prophylaxis.
• Older adults: low starting doses and watch for hypotension and bradycardia.
• Kidney or liver impairment: reduce diltiazem, verapamil and amlodipine doses in severe hepatic impairment.