Myocardial Infarction with Nonobstructive Coronary Arteries

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is infarction, with a troponin rise or fall and evidence of infarction, in a patient whose angiogram shows no epicardial stenosis of 50% or more. It is a working diagnosis that needs a cause to be sought.

It accounts for about 5 to 6% of infarctions, and more in women (up to three times as often) and younger patients. It is a heterogeneous group, not a single disease.

Causes are plaque disruption with minor stenosis, epicardial or microvascular spasm, coronary microvascular dysfunction, coronary embolism or in situ thrombosis, and spontaneous coronary artery dissection.

Non-ischaemic causes of troponin rise (myocarditis, takotsubo syndrome, other cardiomyopathy, pulmonary embolism, sepsis) look the same at first and must be excluded before the label is kept.

Outcome is better than infarction with obstructive disease in most registries, but recurrent angina, infarction and heart failure are common.

Pathophysiology. Mechanisms are ischaemic: erosion or rupture of a non-obstructive plaque with transient thrombus, hyperreactive smooth muscle, impaired microvascular dilatation, or thromboembolism. A supply demand mismatch can also contribute.

• Chest pain, dyspnoea, sweating, in a younger patient, often a woman, with fewer risk factors.
• ST elevation in a proportion, and ST depression or T wave change in others.
• Triggers: tobacco, cocaine, cannabis, fluoropyrimidine chemotherapy, emotional stress, pregnancy or the postpartum period, connective tissue disease, fibromuscular dysplasia, migraine and Raynaud phenomenon (spasm).
• Features of thrombophilia, preceding viral illness, or recent immune checkpoint inhibitor use.

Red flags.

• Cardiogenic shock or ventricular arrhythmia
• ST elevation with a non-obstructive angiogram
• Recurrent or prolonged chest pain, or recurrent infarction
• Pregnancy or the postpartum period
• Cocaine or other stimulant use
• Reduced ejection fraction

• Confirm the infarction criteria with serial high sensitivity troponin and ECG. Repeat ECG during pain.
• Review the angiogram carefully for spontaneous dissection, thrombus, ectasia, bridging and spasm. Left ventriculography for the wall motion pattern.
• Intracoronary imaging. Optical coherence tomography or intravascular ultrasound shows plaque rupture, erosion, calcified nodule, dissection or thrombus, and identifies a cause in a large share.
• Cardiac MRI within 1 to 2 weeks, with oedema and late gadolinium enhancement. Subendocardial or transmural enhancement in a coronary territory means infarction. Mid-wall or subepicardial enhancement means myocarditis. Apical or mid-ventricular ballooning with oedema and no enhancement means takotsubo syndrome. It identifies the cause in most patients.
• Echocardiography for wall motion and ejection fraction.
• Provocative spasm testing and coronary function testing when the mechanism is unclear, not during the acute phase and not in unstable patients. Intracoronary acetylcholine in escalating doses (most regimens use 2, 20 and 100 microgram, and some add 200 microgram) with 3 minutes between steps. Spasm is a diameter reduction of 90% or more with symptoms and ischaemic ECG change. Coronary flow reserve under 2.0, or an index of microcirculatory resistance of 25 or more, shows microvascular dysfunction. Contraindicated in left main disease, severe hypotension, heart failure, bradycardia and severe asthma.
• Thrombophilia and other workup: lupus anticoagulant, anticardiolipin and anti-beta-2 glycoprotein I antibodies, full blood count, toxicology, ESR and CRP, and CT or MR angiography of the head, neck, abdomen and pelvis for fibromuscular dysplasia when dissection is shown.

Differential diagnosis.

• Myocarditis
• Takotsubo syndrome
• Type 2 myocardial infarction
• Pulmonary embolism
• Aortic dissection
• Sepsis related and other non-ischaemic myocardial injury
• Hypertrophic and other cardiomyopathy

Acute phase. Give aspirin 300 mg orally once and anticoagulation with enoxaparin 1 mg/kg subcutaneously every 12 hours (1 mg/kg once daily at creatinine clearance under 30 mL/min) until the mechanism is clear. Anticoagulation and fibrinolysis are stopped, or withheld, once spontaneous dissection is found. Then direct treatment by cause.

• Plaque disruption. Aspirin 75 to 100 mg orally once daily long term (usual maximum 325 mg daily) with a P2Y12 inhibitor for up to 12 months (clopidogrel 75 mg once daily, or ticagrelor 90 mg twice daily, benefit unproven). Atorvastatin 40 to 80 mg once daily, with liver enzymes at baseline and 3 months, and LDL cholesterol under 1.4 mmol/L (55 mg/dL). Ramipril 2.5 mg once daily, increased every 2 to 4 weeks to 10 mg once daily (maximum 10 mg daily, 5 mg daily at creatinine clearance under 30 mL/min), with potassium and creatinine 1 to 2 weeks after each change. Bisoprolol 2.5 mg once daily increased to 5 to 10 mg once daily (maximum 20 mg daily; do not exceed 10 mg daily at creatinine clearance under 20 mL/min or in severe liver impairment).
• Vasospasm. Diltiazem 60 mg orally every 8 hours (modified release 180 to 360 mg once daily), maximum 360 mg daily, or amlodipine 5 mg once daily increased to 10 mg (maximum 10 mg daily). Add isosorbide mononitrate modified release 30 mg once daily increased to 60 mg (maximum 120 mg daily) in the morning, with glyceryl trinitrate 400 microgram sublingually for attacks. Avoid non-selective beta blockers, triptans, tobacco, cocaine and amphetamines. Do not stop calcium channel blockers abruptly. Continue for at least 6 to 12 months.
• Microvascular dysfunction. Bisoprolol 2.5 mg once daily increased to 5 to 10 mg once daily (maximum 20 mg daily), a calcium channel blocker (diltiazem 60 mg orally every 8 hours, maximum 360 mg daily), and ramipril 2.5 mg once daily increased to 10 mg once daily. Ranolazine 375 mg twice daily, increased to 500 mg twice daily, maximum 750 mg twice daily (1,000 mg twice daily in some labels), with the contraindications of cirrhosis, creatinine clearance under 30 mL/min and strong CYP3A4 inhibitors.
• Thromboembolism. Anticoagulation by source, with apixaban for atrial fibrillation: 5 mg orally twice daily, reduced to 2.5 mg twice daily when at least two of age 80 years or over, weight 60 kg or under and serum creatinine 133 micromol/L or over are present, also 2.5 mg twice daily at creatinine clearance 15 to 29 mL/min and avoided under 15 mL/min, maximum 10 mg daily. Antiphospholipid syndrome: warfarin to an INR of 2.0 to 3.0, with direct oral anticoagulants avoided.
• Spontaneous coronary artery dissection. Conservative management when stable. Aspirin 75 to 100 mg once daily for up to 12 months, and bisoprolol 2.5 mg once daily increased to 5 to 10 mg once daily (maximum 20 mg daily). Revascularisation only for ongoing ischaemia, left main involvement or instability. Avoid fibrinolysis and, unless there is thrombus or another indication, anticoagulation. Screen for fibromuscular dysplasia. Counsel against pregnancy.
• Myocarditis or takotsubo syndrome on MRI. The diagnosis changes, and treatment follows that disease.
• Lifestyle and rehabilitation. Stop smoking and stimulants, treat depression, and give cardiac rehabilitation.

Special groups.

• Women: more frequent. Look specifically for dissection, spasm and microvascular disease.
• Pregnancy and postpartum: spontaneous dissection is the leading cause. Avoid statins, ACE inhibitors and thrombolysis, and use low dose aspirin and a beta blocker (metoprolol tartrate 25 to 100 mg orally twice daily, maximum 200 mg daily in this setting).

Monitoring. Echocardiography at discharge and at 3 months. Cardiac MRI at 1 to 2 weeks if not done. Symptoms and blood pressure at 1, 3 and 12 months. Repeat antiphospholipid testing at 12 weeks. Potassium and creatinine 1 to 2 weeks after each change of ramipril.

Referral and escalation. Refer to cardiology and a centre that offers intracoronary imaging and cardiac MRI. Urgent for shock, arrhythmia, recurrent chest pain or reduced ejection fraction.