Key Principles

• Functional coronary angiography is an invasive guidewire-based procedure utilising pharmacological vasoactive agents to assess small and large coronary vasomotor dysfunction.
• It is indicated in patients with ischaemic syndromes without an explanation for their symptoms, i.e., absence of obstructive coronary artery disease on conventional structural angiography.
• Microvascular dysfunction assessment involves evaluating coronary blood flow responses to adenosine-induced hyperaemia. Large vessel dysfunction assessment is via coronary artery spasm provocation testing with intracoronary acetylcholine bolus doses. Microvascular spasm is diagnosed if acetylcholine induces ischaemia (i.e., chest pain and electrocardiogram [ECG] changes) in the absence of large vessel spasm.
• These tests are supported by recently revised American and European professional society guidelines.
• We outline a standardised functional coronary angiogram protocol that is recommended for Australian and New Zealand cardiac catheterisation laboratories.

Introduction

Ischaemic heart disease (IHD) is a leading global cause of disability and death. The traditional IHD paradigm focuses upon obstructive atherosclerosis driving major adverse cardiac events. However, up to half of the patients undergoing elective angiography for suspected angina and/or demonstrable ischaemia have no obstructive coronary artery disease (CAD) and should be diagnosed as angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). Furthermore, 5%–10% of acute myocardial infarction patients have no evidence of obstructive CAD at angiography and thus diagnosed as myocardial infarction with non-obstructive coronary arteries (MINOCA). These are working diagnoses whereupon the underlying mechanism(s) responsible for the presenting symptoms are further investigated. The clinical definitions for these acute and chronic coronary syndromes are summarised in Table 1.

Disorders of coronary vasomotion, including microvascular- and/or vasospastic angina, may be responsible for the ANOCA/INOCA or MINOCA presentations but are frequently overlooked by conventional diagnostic coronary imaging such as invasive coronary angiography or computed tomography (CT) coronary angiography. These forms of ‘structural coronary angiography’ focus on anatomical epicardial artery atherosclerotic disorders, whereas ‘functional coronary angiography’ evaluates functional disorders of the coronary circulation. Functional coronary angiography involves invasive guidewire-based assessment of the coronary epicardial and microcirculatory vasculature using pharmacological vasoactive agents to assess small/large vessel relaxation and propensity to spasm (Figure 1). Typically, responses to adenosine and acetylcholine (ACh) are sequentially assessed. In patients with angina or myocardial infarction who have flow limiting obstructive CAD excluded on angiography, the cardiac catheterisation laboratory visit is an ideal opportunity to resolve diagnostic uncertainty and provide a clear treatment approach to improve patient outcomes. Providing a diagnosis during the index procedure is cost-effective and offers an efficient approach to healthcare resource utilisation.

Figure 1. Overview of functional coronary angiography. The current established main clinical indications for performing tests of coronary vasomotor disorders may be broadly grouped into three categories. These including patients with INOCA, patients with MINOCA, and patients following OHCA where no clear alternative cardiac cause can be found. The categories are described as (i) INOCA, ischaemia but no obstructive CAD. Patients with INOCA may present with angina, exertional or resting chest discomfort and/or breathlessness, exertional fatigue, nausea, sweating. The discomfort/pressure may be felt in the jaw, neck, arms or shoulders/back. After testing GTN is used to return the coronary arteries to a state of maximal vasodilation. (ii) OHCA, out of hospital cardiac arrest. This can occur in certain scenarios (ventricular arrhythmias/resuscitated cardiac arrest) where no clear cardiac cause can be found, and the patient is stabilised. This is typically in patients with normal LV function as patients with reduced LV function may have suffered from transient malignant ventricular arrhythmia. The guideline supported indications for testing in OHCA include those without significant LV systolic dysfunction, no obstructive CAD, normal ECG. (iii) MINOCA, myocardial infarction without obstructive CAD. Infarction without culprit stenosis where vasospastic or microvascular angina are considered. Abbreviations: CAD, coronary artery disease; CFR, coronary flow reserve, ECG, electrocardiogram; FFR, fractional flow reserve; GTN, glyceryl trinitrate; IMR, index of microcirculatory resistance; INOCA, ischaemia but no obstructive coronary artery disease; LV, left ventricular; LVEDP, left ventricular end-diastolic pressure; MINOCA, myocardial infarction but without obstructive coronary artery disease; OHCA, out-of-hospital cardiac arrest.

Recent European Society of Cardiology (ESC) Chronic Coronary Syndrome guidelines have emphasised the diverse mechanisms responsible for myocardial ischaemia, highlighting the importance of INOCA. When the coronary circulation is comprehensively assessed in patients with INOCA, as many as four in five patients may have evidence of microvascular or vasospastic angina. INOCA is prevalent in both men and women, however a potential gender bias exists whereby INOCA is more common in women. The syndrome affects quality of life and has adverse prognostic implications. MINOCA and type II myocardial infarction have significant overlap and propensity to coronary artery spasm may be the unifying diagnosis. Recent ESC and American College of Cardiology/American Heart Association (ACC/AHA) guidelines support the use of functional coronary angiography in INOCA and MINOCA. Despite this, testing for disorders of coronary vasomotion is performed in very few centres in Australia and New Zealand.

We aim to provide a standardised functional coronary angiography protocol for adoption in Australia and New Zealand, as agreed upon by members of the Cardiac Society of Australia and New Zealand (CSANZ) Coronary Vasomotor Dysfunction Working Group. This will (a) facilitate an increased awareness and diagnosis of INOCA/MINOCA syndromes, (b) provide a benchmark diagnostic approach thereby ensuring appropriate interpretation of results with respect to established diagnostic criteria, and (c) promote collaborative research, involving patients with common clinical criteria. The details of the CSANZ Functional Coronary Angiography protocol are outlined, with recommendations summarised in Table 2 and illustrated in Figure 2.

Figure 2. Functional coronary angiography protocol: a proposed step-by-step approach to guidewire-based assessment of coronary vascular function using thermodilution or Doppler and then vasoreactivity testing using acetylcholine. This simple approach focuses on thermodilution which is straightforward to include during daily practice. Note: The cut off for HMR values for diagnosis of microvascular disease in angina is typically ≥2.5 for CMD diagnosis however others consider a less stringent HMR cut off for CMD diagnosis as ≥1.9. Microvascular spasm is the reproduction of angina chest pain with ACh testing including ischaemic ECG changes in the absence of significant epicardial vessel constriction. Epicardial spasm is the reproduction of angina chest pain with ACh testing including ischaemic ECG changes in the presence of significant (subtotal – >90% epicardial vessel). ˆ The 50 mcg dose is optional and may progress directly to 100 mcg. + Assess chest pain, ischaemic ECG changes and coronary constriction after each dose. # Positive Test = chest pain with ischaemic ECG changes and >90% constriction. ∗ Test for RCA spasm in the absence of LCA spasm. Requires temporary pacemaker insertion. Created in BioRender. Watts, M. (2025) https://biorender.com/cqwz5ir.
Abbreviations: ACh, acetylcholine; CFR, coronary flow reserve; CMD, coronary microvascular dysfunction; ECG, electrocardiogram; GTN, glyceryl trinitrate; HMR, hyperaemic microvascular resistance; IMR, index of microcirculatory resistance; LCA, left coronary artery; LVEDP, left ventricular end-diastolic pressure; RCA, right coronary artery.