The purpose of this practical guide is to provide information on the preparation and administration of an interventional diagnostic procedure in clinical practice. It discusses some key preparation and safety considerations, as well as tips for procedural success.
Approximately 40% of patients undergoing invasive coronary angiography for investigation of angina are found to have no obstructive coronary artery disease (ANOCA). Abnormal coronary function underlies coronary vasomotion syndromes including coronary endothelial dysfunction, microvascular angina, vasospastic angina, post-PCI angina and myocardial infarction with no obstructive coronary arteries (MINOCA). Each of these endotypes are distinct subgroups, characterized by specific disease mechanisms. Diagnostic criteria and linked therapy for these conditions are now established by expert consensus and clinical guidelines.
Coronary function tests are performed as an adjunctive interventional diagnostic procedure (IDP) in appropriately selected patients during coronary angiography. This aids differentiation of patients according to endotype. The IDP includes two distinct components: a diagnostic guidewire test and a pharmacological coronary reactivity test. The tests last approximately 5 minutes for the former and 10-15 minutes for the latter. Patient safety and staff education are key.
The diagnostic guidewire test measures parameters of coronary flow limitation (fractional flow reserve [FFR], coronary flow reserve [CFR], microvascular resistance [index of microvascular resistance (IMR)], basal resistance index, and vasodilator function [CFR, resistive reserve ratio (RRR)]).
The pharmacological coronary reactivity test measures the vasodilator potential and propensity to vasospasm of both the main coronary arteries and the micro-vessels. It involves intra-coronary infusion of acetylcholine and glyceryl trinitrate (GTN). Acetylcholine is not licensed for parenteral use and is therefore prescribed on a named-patient basis. Vasodilatation is the normal, expected response to infusion of physiological concentrations of acetylcholine. Vascular spasm represents an abnormal response, which supports the diagnosis of vasospastic angina.
The purpose of this practical guide is to provide information on the preparation and administration of the IDP in clinical practice. It discusses some key preparation and safety considerations, as well as tips for procedural success. The IDP supports stratified medicine for a personalized approach to health and wellbeing.
Approximately 40% of patients undergoing invasive coronary angiography for investigation of suspected angina are found to have no obstructive coronary artery disease (ANOCA)1. Anatomical imaging in coronary angiography has a spatial resolution of approximately 0.3 mm, which lacks sensitivity in visualizing the resistance arterioles that help to govern myocardial blood flow2. Supply/demand mismatch of myocardial blood flow relative to requirements may induce ischemia and drive angina symptom burden.
Coronary function testing provides information on the health of the coronary circulation, the presence and nature of abnormal coronary function. The goal of testing is therefore to aid in the diagnosis of coronary vasomotion disorders. These include coronary endothelial dysfunction, microvascular angina, vasospastic angina, post-percutaneous coronary intervention (PCI) angina and myocardial infarction with non-obstructive coronary arteries (MINOCA). These conditions are associated with impaired quality of life, higher morbidity and healthcare resource utilization3,4,5.
Coronary function tests are performed either as an adjunctive interventional diagnostic procedure (IDP) at the time of invasive coronary angiography, or non-invasively by cardiac MRI or transthoracic Doppler echocardiography. Its role within the diagnostic pathway has been discussed elsewhere6. Diagnostic criteria and linked therapy for the different endotypes of coronary vasomotion disorders are now established by expert consensus7 and clinical guidelines8,9.
Despite the advent of guidelines and objective testing, there remains variation in clinical practice for the diagnosis and management of this heterogenous group of patients. An alternative approach to coronary function testing is to institute a trial of therapy in all patients. Proponents of this approach cite a shorter procedural duration and reduced upfront cost from the procedural diagnostic guidewires and pharmacological testing agents.
However, stratifying patients by the differing disease mechanisms and personalizing their therapies is an approach that better aligns with the concept of precision medicine10. Indeed, the CorMicA trial served evidence that this approach may improve angina and quality of life in patients with ANOCA11,12.
Here, we present a protocol for an IDP to assess coronary vasomotor function. It is intended to enhance diagnostic power in the cardiac catheterization laboratory for patients with ANOCA.
General considerations for the IDP
The IDP includes two distinct components6: a diagnostic guidewire test and a pharmacological coronary reactivity test. A common approach is to perform these tests in sequence, with acetylcholine administered before the diagnostic guidewire is withdrawn. The benefit of this approach is that the guidewire will stabilize the guide catheter, which in turn helps to ensure selective intracoronary infusion of acetylcholine and GTN.
The multidisciplinary team should involve an interventional cardiologist with prior experience of the acetylcholine test protocol, supported by the catheter laboratory team, including nurses, a physiologist, and a radiographer. Involving a second cardiologist may be helpful. The tests last approximately 5 minutes for the diagnostic guidewire component and 10-15 minutes for the pharmacological component.
Patient selection
The IDP is performed at the time of invasive coronary angiography, either as a planned procedure or as an ad-hoc "follow-on" if no obstructive coronary artery disease is found, with the condition that informed consent has been obtained. The patient should be aware of the additional risks and benefits of the adjunctive interventional diagnostic procedure. Unless contraindicated, most patients undergoing investigation for possible angina may be considered. This is particularly helpful in patients who have had previous anatomical imaging (invasive or otherwise) to suggest the possibility of ANOCA.
Advanced renal dysfunction, where contrast media administration may be detrimental to renal function, is a relative contraindication to invasive angiography. Relative contraindications to acetylcholine testing include severe chronic obstructive pulmonary disease (COPD) and obstructive coronary artery disease (CAD). Vasoactive medications (such as beta-blockers, calcium channel blockers, and nitrates) and caffeine-containing drinks should be withheld for at least 24 hours pre-procedure.
The diagnostic guidewire
Current diagnostic guidewires utilize a combined technology of a pressure sensor with either: 1) a temperature sensor to estimate flow based on the principles of thermodilution, or 2) an ultrasound sensor to estimate flow based on the Doppler principle. Thermodilution-based wires are safe and straightforward to use11. Doppler/pressure wires may have higher accuracy and better correlation with non-invasive testing results, but at the expense of wire maneuverability13. This review focuses on thermodilution-based guidewires.
The pharmacological reactivity test
Pharmacological tests of coronary reactivity involve intracoronary infusion of acetylcholine and glyceryl trinitrate (GTN), to assess the vasodilator potential and propensity to vasospasm of the main coronary arteries and microcirculation. Vasodilatation is the normal, expected response to infusion of physiological concentrations of acetylcholine. Vascular spasm represents an abnormal response, which would support the diagnosis of vasospastic angina. Okumura et al. demonstrated that intracoronary acetylcholine had 90% sensitivity and 99% specificity for diagnosing epicardial spasm14.
Safety considerations
The half-life of acetylcholine is 1-2 seconds. Any physiological responses will cease within 5-10 seconds. More than three decades of experience with intracoronary acetylcholine tests support overall procedural safety. Self-limiting bradycardia and heart block are to be expected. These effects may be more profound if acetylcholine is infused into the dominant coronary artery, but should nonetheless be transient.
Atropine should be at hand, ready for administration, however the short half-life of acetylcholine means that it is rarely required. A simple cough maneuver by the patient is usually sufficient to restore sinus rhythm. Shortening of the atrial refractory period and increased propensity to atrial fibrillation (<10%) can occur, but this is typically short lived.
A review by Sueda et al. found a rate of 0.6% for major complications, such as ventricular tachycardia, cardiac tamponade and shock with intracoronary acetylcholine15. More recent experience in the CorMicA study11 did not reveal any serious adverse events secondary to the IDP. Together, these findings reinforce the importance of informed consent. Acetylcholine should be pre-ordered by a cardiologist on a named patient basis from the pharmacy.
Thromboprophylaxis and loading with antiplatelet therapy
Standard coronary angiography is associated with a small risk of thromboembolism. Subclinical micro-emboli may occur, as revealed by transcranial Doppler studies16. Further, guidewire-based coronary instrumentation carries a very small risk of vascular injury, which may in turn necessitate PCI. Therefore, platelet inhibition may be considered for thromboprophylaxis at the time of the procedure, and to optimize patient safety. Indeed, the pre-procedural clinical plan for some of these patients may already include antiplatelet therapy, due to the possibility of obstructive coronary artery disease and/or PCI at the time of angiography. Since radial artery access is routinely used, the risks of bleeding are considered minimal. There is no interaction anticipated between dual antiplatelet therapy, including a loading dose of aspirin and clopidogrel, and the coronary response to acetylcholine.
The following protocol adheres to the guidelines of our institution's human research ethics committee. Methods from this protocol have been included within ethics committee-approved research studies in our institution17,18.
1. Coronary angiography
2. Diagnostic guidewire test (FFR, CFR, IMR, RRR)
3. Pharmacological reactivity test
4. Multivessel assessment
The ultimate goal of the IDP is to be able to differentiate patients according to their respective clinical endotypes and institute appropriate management. The main endotypes to consider are: microvascular angina, vasospastic angina, mixed (both), or non-cardiac symptoms. The individual endotypes and diagnostic criteria are summarized in Table 1. Figure 1 further illustrates how these criteria are applied at each step of the IDP, with examples of abnormal results.
Diagnostic guidewire test
The diagnostic guidewire test measures parameters of coronary flow limitation (fractional flow reserve [FFR], coronary flow reserve [CFR], microvascular resistance [index of microvascular resistance (IMR)], basal resistance index, and vasodilator function [CFR, resistive reserve ratio (RRR)]). Abnormal results are defined below:
FFR ≤0.80 is indicative of obstructive epicardial disease.
CFR <2.0 (2.0-2.5 = 'grey zone') in the absence of obstructive epicardial disease is indicative of microvascular angina.
IMR ≥25 is indicative of microvascular angina.
RRR<2.0 is indicative of microvascular angina.
Acetylcholine provocation test
A clinical response is reflected by concomitant symptoms (i.e., chest pain), changes on the ECG (i.e., ST-segment deviation) and/or angiogram (Figure 1). Abnormalities on the coronary angiogram include: reduction in coronary artery diameter when assessed visually or measured by quantitative coronary analysis (QCA), transient impairment in antegrade coronary flow (TIMI flow), and a reduced myocardial blush.
Vasospastic angina symptoms typically occur at rest, may exhibit marked diurnal variation, and may be precipitated by hyperventilation19. The European Association of Percutaneous Cardiovascular Interventions (EAPCI)9 and Japanese Circulation Society (JCS)19 have proposed standardized criteria for the diagnosis of vasospastic angina. These are summarized in Table 1. Recognition of vasospastic angina is important due to its associated increased risk of myocardial infarction19.
Vasospastic angina is diagnosed when there is ≥90% reduction in coronary luminal diameter, along with reproduction of anginal symptoms and ischemic ECG changes.
Microvascular spasm is diagnosed with the reproduction of angina, ST-segment deviation, <90% change in epicardial lumen diameter, and/or TIMI flow reduction.
Table 1: Diagnostic criteria for each endotype (disease sub-group). Please click here to download this Table.
Figure 1: Summary flow-chart for interpretation of IDP results, with illustrative examples. IMR, index of microvascular resistance; CFR, coronary flow reserve. Please click here to view a larger version of this figure.
Nitrate administration after radial artery cannulation reduces the propensity towards peripheral vasospasm that might hamper catheter manipulation. Intracoronary nitrates prior to diagnostic guidewire testing serves to negate any confounding epicardial spasm. Bearing the subsequent pharmacological provocation test in mind, only short-acting nitrates (e.g., GTN) are used. With a short half-life of approximately 2 minutes, the majority of this drug is metabolized prior to the later commencement of acetylcholine infusion20. In our experience, this has not led to false negative pharmacological test results.
Guide catheter choice should be personalized to achieve the best balance between support and patient tolerability. The benefits of good catheter support include: reduced variation in volume delivered from each saline bolus, reduced risk of vessel injury due to less recoil of the catheter during rapid saline injections, and reduced transit time variability by stabilizing the diagnostic guidewire position within the vessel. ‘Balloon-tracking’, or alternatively ‘catheter-assisted tracking’ by advancing a 5 Fr diagnostic pigtail catheter within a 6 Fr guide, can help overcome issues with shearing injury and radial spasm6.
Provision of a dedicated 3 mL syringe may assist with thermodilution injections. When inspecting results for artefact and outliers, a ≤10% (or ≤0.1 s) variation between thermodilution transit times represent good consistency. Thermodilution deflection waveforms should be of similar shape and overlap.
If significant signal drift repeatedly occurs during measurement, check that all elements within the catheter and manifold system are secure. ‘Pressure bleed’ can occur from loose connections to the pressure transducer.
The authors have nothing to disclose.
The authors are grateful to the patients, colleagues and institutions that have contributed to the body of knowledge in this field. No specific funding was received for this work.
Coroflow software | Coroventis | N/A | https://www.coroventis.com/coroflow/measurements-indepth/ |
Miochol-E, 20 mg, Powder and Solvent for instillation solution for intraocular use. | Bausch & Lomb U.K Limited | Unlicensed for parenteral use | https://www.medicines.org.uk/emc/product/4795/smpc#gref |
PressureWire Receiver | Abbott Vascular | C17040 | https://www.cardiovascular.abbott/us/en/hcp/products/percutaneous-coronary-intervention/pressurewireX-guidewires-physiology/ht-tab/ordering-info.html |
PressureWire X Guidewire, 175 cm | Abbott Vascular | C12059 | https://www.cardiovascular.abbott/us/en/hcp/products/percutaneous-coronary-intervention/pressurewireX-guidewires-physiology/ht-tab/ordering-info.html |