Ischaemia with Nonobstructive Coronary Arteries

Ischaemia with non-obstructive coronary arteries (INOCA) is angina or objective myocardial ischaemia in a patient whose coronary arteries have no stenosis of 50% or more, with fractional flow reserve over 0.80 and instantaneous wave free ratio over 0.89 where measured.

It is common. Up to half of patients with angina who have angiography have no obstructive disease, and the proportion is higher in women.

Endotypes are coronary microvascular angina (impaired vasodilatation or structural disease), vasospastic angina (epicardial or microvascular spasm), and mixed disease. Prognosis is not benign: risk of infarction, admission with chest pain, heart failure with preserved ejection fraction, and poor quality of life are increased.

Pathophysiology. Impaired endothelium dependent and independent dilatation, microvascular remodelling and rarefaction, and smooth muscle hyperreactivity reduce flow reserve. Risk factors are diabetes, hypertension, obesity, smoking, inflammatory disease and oestrogen deficiency after menopause.

• Effort angina, prolonged episodes, rest angina, and early morning or nocturnal pain (spasm). Variable response to nitrates.
• Dyspnoea, fatigue and reduced exercise capacity.
• Associations: Raynaud phenomenon, migraine, hypertension, diabetes, obesity, previous gestational complications.
• Examination and resting ECG are usually normal. Transient ST change occurs during spasm.

• Clinical and risk assessment. Pre-test probability, risk factors, medication review (including triptans, fluoropyrimidines).
• Exclude obstructive disease. CT coronary angiography, with CT-derived flow reserve where available.
• Non-invasive ischaemia and flow testing. Stress perfusion MRI or PET with myocardial flow reserve (under 2.0 abnormal, some use under 2.5), stress echocardiography, and Doppler of the left anterior descending artery for flow velocity reserve (under 2.0 abnormal).
• Invasive coronary function testing when symptoms persist and the cause affects treatment:
  • Pressure and temperature wire with intracoronary adenosine: coronary flow reserve under 2.0 (some use under 2.5) and index of microcirculatory resistance of 25 or more indicate microvascular dysfunction.
  • Intracoronary acetylcholine in escalating doses (most regimens use 2, 20 and 100 microgram, and some add 200 microgram). Epicardial spasm is a diameter reduction of 90% or more with symptoms and ECG change. Microvascular spasm is symptoms and ischaemic ECG change with less than 90% constriction.
  • Contraindicated in left main disease, severe hypotension, heart failure, bradycardia and severe asthma.
• Laboratory. Lipids, HbA1c, thyroid function, haemoglobin, CRP, and an inflammatory or autoimmune screen when indicated.
• Echocardiography for ejection fraction, diastolic function and left ventricular hypertrophy.

Differential diagnosis.

• Functionally significant obstructive coronary disease
• Myocardial infarction with non-obstructive coronary arteries
• Heart failure with preserved ejection fraction
• Hypertrophic cardiomyopathy and aortic stenosis
• Takotsubo syndrome, myocarditis and pericarditis
• Myocardial bridging
• Oesophageal spasm and gastro oesophageal reflux
• Anaemia and thyrotoxicosis
• Musculoskeletal pain, anxiety and panic disorder

Therapy directed by the endotype found on testing improves angina and quality of life more than usual care.

• All patients. Smoking cessation, exercise and cardiac rehabilitation, weight loss, blood pressure under 130/80 mm Hg, and glucose control. Atorvastatin 20 to 40 mg orally once daily (liver enzymes at baseline and 3 months, avoided in pregnancy). Aspirin 75 to 100 mg once daily only when atherosclerotic plaque is shown on imaging. Ramipril 2.5 mg orally 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), for hypertension or diabetes, with potassium and creatinine 1 to 2 weeks after each change. Contraindicated in pregnancy and bilateral renal artery stenosis.
• Microvascular angina.
  • Bisoprolol 2.5 mg orally 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).
  • Amlodipine 5 mg once daily, increased to 10 mg (maximum 10 mg daily), or diltiazem 60 mg orally every 8 hours (maximum 360 mg daily) when a beta blocker is not tolerated.
  • Ranolazine 375 mg orally twice daily, increased after 2 to 4 weeks to 500 mg twice daily, maximum 750 mg twice daily (1,000 mg twice daily in some labels). Contraindicated in cirrhosis, at creatinine clearance under 30 mL/min and with strong CYP3A4 inhibitors. Monitor QTc.
  • Isosorbide mononitrate modified release 30 mg once daily in the morning, increased to 60 mg (maximum 120 mg daily), for symptoms, though nitrate response is variable.
  • Refractory disease: specialist options (coronary sinus reducer, spinal cord stimulation) have limited evidence.
• Vasospastic angina.
  • Calcium channel blockers are first line: diltiazem 60 mg orally every 8 hours (maximum 360 mg daily) or amlodipine 5 to 10 mg once daily (maximum 10 mg daily).
  • Add isosorbide mononitrate modified release 30 mg once daily increased to 60 mg (maximum 120 mg daily) with a nitrate free interval when the calcium channel blocker alone fails. Glyceryl trinitrate 400 microgram sublingually for attacks.
  • Avoid non-selective beta blockers, triptans, cocaine, amphetamines, tobacco and fluoropyrimidines where possible. Do not stop calcium channel blockers abruptly. Continue for at least 6 to 12 months before supervised, gradual withdrawal.
  • Defibrillator for resuscitated arrest from spasm.
• Heart failure with preserved ejection fraction overlap. Dapagliflozin 10 mg orally once daily (start at eGFR 25 mL/min/1.73 m2 or more, contraindicated in type 1 diabetes, withhold during acute illness with poor oral intake).
• Coronary imaging is repeated only with a change in symptoms.

Special groups.

• Women: the commonest group. Hormone therapy is not used for angina.
• Diabetes: strict glycaemic and blood pressure control, with an SGLT2 inhibitor when heart failure or kidney disease is present.

Monitoring. Symptom diary and review at 4 to 6 weeks after each change, then every 3 to 6 months. Blood pressure, lipids and HbA1c at each visit as indicated. ECG for QTc on ranolazine. Repeat testing only if symptoms change.

Referral and escalation. Refer to a cardiology service with coronary function testing for persistent symptoms despite treatment. Urgent for rest angina with ST change, resuscitated arrest or falling ejection fraction.