Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function
March 15th, 2022
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.
Many patients with angina have no obstructive coronary artery disease at the time of angiography. This is also known as INOCA. Here, we present a comprehensive gold standard protocol for testing structural and functional disorders of the coronary circulation.
This technique comprises two components, the diagnostic guidewire study, as well as the acetylcholine provocation test. Together, they provide additional information to help distinguish between the INOCA endotypes. This technique is therefore useful for investigating patients for potential microvascular angina and/or vasospastic angina.
This then allows for personalization of therapies according to diagnosis. Performing the procedure with us today is Professor Colin Berry. It's my pleasure to introduce Professor Berry, who is a professor of cardiology at the University of Glasgow and a consultant cardiologist at the Golden Jubilee National Hospital.
Before starting, review the clinical case and plan the procedure with the catheter laboratory team. Prepare medication and equipment in case of adverse events. To begin the procedure, obtain arterial access using the standard Seldinger technique.
Administer modest doses of intra-arterial, short-acting nitrate to reduce the propensity of radial artery spasm. Then, record the left ventricular and diastolic pressure and perform standard coronary angiography to obtain orthogonal views of all main coronary artery branches. Engage the coronary artery with a guide catheter.
Then, with the guide catheter engaged and coaxial, administer 200 micrograms of glyceryl trinitrate to attenuate any epicardial coronary spasm. Ensure that the activated clotting time is approximately 250 seconds before instrumentation of the coronary artery. Then, move the sensor to the tip of the guide catheter while avoiding handling the diagnostic guidewire sensor.
Then, flush the guide catheter to avoid contrast pressure damping. Wait 30 seconds for resting conditions to return before equalizing the pressure with the invasive aortic root pressure. Advance the diagnostic guidewire to the distal third of the coronary artery.
With the diagnostic guidewire in a suitable position within the vessel, flush the guide catheter with room-temperature saline and wait 30 seconds for resting physiology to return. Record resting pressure indices, including resting PdPa and RFR. Next, use a three-milliliter syringe to administer brisk three-milliliter boluses of room-temperature normal saline via the guide catheter.
Repeat the three-milliliter boluses of room-temperature normal saline as required. Inspect the recorded transit times and replace any outlier readings. Set up the linked diagnostic software and commence IV adenosine infusion at 140 micrograms per kilograms per minute via a large peripheral venous cannula.
Monitor for signs of hyperemia. Document fractional flow reserve at stable hyperemia. While the adenosine infusion is ongoing, the software is switched back to the thermodilution CFR/IMR page to complete hyperemic thermodilution measurements.
Repeat rapid three-milliliter boluses of room-temperature normal saline via the guide catheter to record hyperemic thermodilution transit times. Then, stop the IV adenosine. Acquire 1, 10, and 100 micromolar solutions of acetylcholine and keep at four degrees Celsius.
Choose an angiographic projection that allows visualization of the coronary artery, with minimal foreshortening and overlap. Then, acquire a resting angiogram. Check that the guide catheter is coaxially intubated for the acetylcholine infusion.
Next, connect a long, sterile IV line to a three-way tap and flush the system with normal saline. Connect the sterile IV line to a 60-milliliter syringe containing one micromolar acetylcholine. Purge the IV line and guide catheter with four milliliters of acetylcholine solution.
With the guide catheter still coaxial, commence the infusion at two milliliters per minute for two minutes. Monitor the patient for vital signs and ECG for effects of acetylcholine. If encountering safety concerns, stop the acetylcholine infusion immediately.
After each acetylcholine infusion, acquire an ECG and assess the patient for symptoms. Gently purge the guide catheter system with contrast. Repeat the coronary angiogram in the same projection as at rest.
Closely monitor the vital signs and ECG of the patient while the angiographic images are assessed for vasospasm, TIMI flow, and myocardial blush. Next, connect a 60-milliliter syringe to infuse 10 micromolar acetylcholine solution. Commence the infusion at two milliliters per minute for two minutes.
After infusion, acquire an ECG and assess the patient for symptoms. Repeat the coronary angiogram, then perform an acetylcholine infusion using 100 micromolar acetylcholine solution at two milliliters per minute for two minutes. Acquire an ECG, and repeat the coronary angiogram.
With the guide catheter still coaxial, perform manual infusion of acetylcholine for over 20 seconds. This dose is usually 100 micrograms for the left coronary artery, or reduced to 50 micrograms in the right or dominant coronary artery. Repeat the coronary angiogram in the same projection as at rest.
Ensure sufficient time to assess myocardial blush and TIMI frame counts over three heartbeats. After this, administer 300 micrograms of intra-coronary glyceryl trinitrate, and allow 30 seconds for it to take effect. Finally, pull back the diagnostic guidewire and ensure signal drift of less than or equal to 0.03.
Check a final angiogram to exclude distal guidewire injury. The interventional diagnostic procedure is used to differentiate patients according to their clinical endotypes and institute appropriate management. The diagnostic guidewire test measures the parameters of coronary flow limitation.
If the index of microvascular resistance is greater than 25, or if the coronary flow reserve value is less than 2 in the absence of obstructive epicardial disease, it is indicative of microvascular angina. Another example is seen here. Using the acetylcholine provocation test, microvascular spasm is diagnosed with the reproduction of angina, ST-segment deviation, less than 90%change in epicardial lumen diameter, or TIMI flow reduction, as seen in this case.
Vasospastic angina is diagnosed when there is more than 90%reduction in coronary luminal diameter along with reproduction of anginal symptoms and ischemic ECG changes. An example is seen here. There are a few important considerations when performing this technique.
First, beware of hydrodissection or air emboli during injections. Second, ensure that there's close monitoring during the acetylcholine infusions. And finally, ensure that the guide catheter is gently purged after each infusion to avoid a sudden bolus during the next injection.
So, in conclusion, this technique helps to guide the stratification and management of patients with INOCA. Research studies that have utilized this technique include the CorMicA pilot, the Cor-CTCA study, and the ongoing iCorMicA trial.
Overview
This practical guide outlines the preparation and administration of an interventional diagnostic procedure for patients with angina and no obstructive coronary artery disease. It emphasizes key safety considerations and procedural tips for success.
Key Study Components
Area of Science
- Cardiology
- Interventional procedures
- Diagnostic techniques
Background
- Many patients with angina exhibit no obstructive coronary artery disease.
- This condition is referred to as INOCA (Ischemia with No Obstructive Coronary Artery Disease).
- Understanding the endotypes of INOCA is crucial for personalized therapy.
- The diagnostic guidewire study and acetylcholine provocation test are essential for evaluating coronary circulation disorders.
Purpose of Study
- To provide a comprehensive protocol for diagnosing structural and functional coronary disorders.
- To differentiate between INOCA endotypes.
- To personalize treatment strategies based on specific diagnoses.
Methods Used
- Preparation of medication and equipment for adverse events.
- Standard Seldinger technique for arterial access.
- Administration of intra-arterial nitrates and glyceryl trinitrate.
- Use of diagnostic guidewire and acetylcholine infusion for testing.
Main Results
- Successful differentiation of patients based on clinical endotypes.
- Measurement of coronary flow limitation parameters.
- Identification of microvascular angina and vasospastic angina.
- Establishment of appropriate management strategies.
Conclusions
- The interventional diagnostic procedure is effective for assessing coronary circulation disorders.
- It aids in the personalization of therapies for patients with angina.
- Continued research and protocol refinement are essential for improving patient outcomes.
Frequently Asked Questions
Executive Industry Relevance
For patients with angina and no obstructive coronary artery disease (INOCA), distinguishing between microvascular and vasospastic endotypes is critical for targeted therapy development. This interventional diagnostic procedure enables mechanistic de-risking by quantifying coronary flow limitation and vasoreactivity, supporting predictive confidence in early-stage cardiovascular drug discovery. The approach provides translational biomarkers that bridge functional phenotyping with clinical endotype stratification, informing go/no-go decisions in preclinical and early clinical pipelines.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Scientific Value: Measures fractional flow reserve, coronary flow reserve, and index of microvascular resistance to interrogate therapeutic hypotheses in coronary microvascular dysfunction pathways.
- Operational Value: Provides quantitative, reproducible hemodynamic parameters that enable functional target validation and biological de-risking of vasoactive compound mechanisms.
Screening & Assay Development
- Scientific Value: Uses acetylcholine infusion to assess vasodilator potential and vasospasm propensity, enabling standardized phenotyping of endothelial and smooth muscle function in human coronary arteries.
- Operational Value: Generates dose-response data (1, 10, 100 µM acetylcholine) that support assay reproducibility and scalability for compound screening in vasculotropic drug discovery.
Translational & Preclinical Research
- Scientific Value: Links invasive coronary physiology measurements to clinical endotypes (microvascular angina, vasospastic angina), supporting translational biomarker alignment and disease-relevant system validation.
- Operational Value: Enables risk-adjusted advancement decisions by identifying patients with specific coronary dysfunction phenotypes for enrichment in early-phase clinical trials.
Pipeline & Workflow Integration
The procedure fits within the cardiovascular discovery continuum from target validation through preclinical modeling to early clinical proof-of-concept, particularly for therapies targeting coronary microvascular function or endothelial health.
- Discovery Biology: Supports hypothesis testing of coronary flow limitation mechanisms and pathway clarification in endothelial-dependent and independent vasoregulation.
- Screening: Delivers quantitative outputs (FFR, CFR, IMR, RRR) and vasoreactivity thresholds that enable reliable comparison of test compounds across preclinical and clinical models.
- Analytics: Provides hyperemic and baseline pressure-derived metrics that help teams compare drug effects on coronary flow reserve and microvascular resistance under standardized conditions.
- Translational Research: Connects functional coronary assessments to clinical endotype stratification, informing patient selection and mechanistic de-risking in early clinical development.
- Enterprise Reuse: Establishes a standardized, clinically validated protocol for coronary function assessment that can be reused across multiple drug discovery programs investigating vasculotropic agents.
Operational & Enterprise Impact
- Scientific Value: Delivers predictive confidence in target engagement by quantifying coronary flow limitation and endothelial-dependent vasodilation, reducing mechanistic ambiguity in cardiovascular drug action.
- Operational Value: Ensures procedural standardization and reproducibility through defined acetylcholine dosing, saline bolus protocols, and pressure wire measurements, enabling cross-site data comparability.
- Strategic Value: Improves go/no-go decisions by identifying patients with specific coronary endotypes, reducing late-stage biological risk in vasculotropic drug development.
- Portfolio Impact: Enables risk-adjusted prioritization of compounds based on their effects on coronary flow reserve, microvascular resistance, and acetylcholine-induced vasoreactivity.
Implementation Considerations
- Requires expertise in interventional cardiology and pressure wire physiology for accurate sensor placement and hemodynamic interpretation.
- Dependent on invasive coronary angiography infrastructure, including guide catheters, pressure wires, and intravenous infusion systems for adenosine and acetylcholine.
- Necessitates cross-functional standardization between cardiology, catheter lab staff, and research teams to ensure consistent acetylcholine dosing, purging protocols, and angiographic timing.
- Adaptation considerations include vessel size adjustments (e.g., reduced acetylcholine dose for right coronary artery) and projection selection to minimize foreshortening during vasospasm assessment.
- Practical limitations include the need for intra-arterial acetylcholine preparation on a named-patient basis due to lack of parenteral licensing, and the requirement for vigilant monitoring during infusions to manage spasm or hypotension risks.
