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.

The following protocol adheres to the guidelines of our institution&#39;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
<ol>
	<li>Before starting, have the catheter laboratory team undertake a &#39;huddle&#39; to review the clinical case and plan the procedure. This includes preparation for medication and/or equipment should adverse events occur (for instance the need for pacing).</li>
	<li>Consider adopting the following checklist: written informed consent, including the off-label use of acetylcholine, indication and potential risks of the procedure, history of allergy, and plan for procedural thromboprophylaxis, sedation and/or pain-control.</li>
	<li>Obtain arterial access using standard Seldinger technique. Radial artery access is recommended as per contemporary guidelines.</li>
	<li>Administer intra-arterial nitrate to reduce propensity to radial artery spasm. Modest doses of short-acting nitrate (e.g., 200 &#181;g of GTN) are recommended. Avoid calcium channel antagonists.</li>
	<li>Give unfractionated heparin 5000 IU and actively manage the activated clotting time (ACT) to ~250 seconds.</li>
	<li>Perform standard coronary angiography to obtain orthogonal views of all main coronary artery branches.</li>
	<li>Record left ventricular end diastolic pressure (LVEDP), if feasible, to provide information on possible alternative explanations for symptoms (e.g., heart failure).</li>
	<li>Size the guide catheter selection according to the patient stature, e.g., 6 Fr and 3.5 size for the standard patient, or 5Fr and 3.0 size for those of smaller stature. 
	&#8203;NOTE: Careful attention to the aortic pressure waveform will inform the operator about &#39;pressure damping&#39; and the risk of coronary dissection. An &#39;Extra Back-Up&#39; catheter may secure a more stable position in the left main coronary artery, but care is needed during manipulation to avoid vessel injury.</li>
</ol>
2. Diagnostic guidewire test (FFR, CFR, IMR, RRR)
<ol>
	<li>Engage the coronary artery with a guide catheter of choice.</li>
	<li>With the guide catheter engaged and co-axial, administer 200 &#181;g of GTN to attenuate any epicardial coronary spasm.</li>
	<li>Ensure that the ACT is ~250 seconds before instrumentation of the coronary artery.</li>
	<li>While avoiding handling the diagnostic guidewire sensor, advance the sensor to the tip of the guide catheter.</li>
	<li>Flush the guide catheter to avoid contrast pressure damping. Allow 30 seconds for resting conditions to return before &#39;equalizing&#39; pressure with the invasive aortic root pressure. Ensure that the catheter system is fully closed (e.g., introducer needle fully removed) and &#39;pressure damping&#39; is not present. Meticulous setup reduces the risk of subsequent errors from &#39;signal drift&#39;.</li>
	<li>Advance the diagnostic guidewire to the distal 1/3 of the coronary artery. In the absence of a clinical indication to select a specific coronary artery, select the left anterior descending (LAD) artery as the default due to the volume of myocardium subtended.</li>
	<li>If encountering difficulty advancing the diagnostic guidewire, consider use of a standard workhorse coronary guidewire as a &#39;buddy-wire&#39;. Alternatively, a different coronary artery may be selected if vascular injury remains a concern.</li>
	<li>With the diagnostic guidewire in appropriate position within the vessel, flush the guide catheter with room-temperature normal saline and allow 30 seconds for resting physiology to return.</li>
	<li>Store a fluoroscopy image of the diagnostic guidewire to document position within the coronary artery.</li>
	<li>Record resting pressure indices, including resting Pd/Pa and RFR.</li>
	<li>Before recording resting thermodilution transit times, flush the guide catheter with room temperature saline to displace saline within the catheter that has been warmed by the patient&#39;s body temperature.</li>
	<li>Using a dedicated 3 mL syringe (or 5 mL syringe in large left dominant coronary arteries), administer brisk 3 mL boluses of room-temperature normal saline via the guide catheter. 
	CAUTION: Care should be taken to avoid injection of air into the coronary artery. Ensure guide catheter is co-axially intubated during injections to avoid hydro trauma.</li>
	<li>Repeat the 3 mL boluses of room-temperature normal saline as required. Inspect the recorded transit times and replace any artefactual and/or outlier readings.</li>
	<li>Set up the linked diagnostic software to prepare for hyperemic measurements. 
	NOTE: For the coronary pressure/flow relationship to become linear, resistance should be minimized and stable. This can be achieved with IV adenosine (140-210 &#181;g/kg/min). Contrast-FFR (ischemic threshold 0.83) is an alternative to FFR with IV adenosine but does not provide the stable hyperemic conditions necessary for thermodilution measurement.</li>
	<li>Inform the patient of potential adenosine side-effects (transient dyspnea, flushing and chest discomfort).</li>
	<li>Commence IV adenosine (140 &#181;g/kg/min) infusion via a large peripheral venous cannula.</li>
	<li>Keep manifold manipulation to a minimum to avoid movement-induced pressure trace artefacts.</li>
	<li>Monitor for signs of hyperemia: &#39;ventriculization&#39; and disappearance of the dicrotic notch in the distal pressure waveform, separation of the aortic and distal pressure waveforms, and symptoms (chest discomfort, dyspnea). Changes in heart rate and blood pressure are less reliable indicators of hyperemia.</li>
	<li>If the initial adenosine infusion fails to achieve steady-state hyperemia, consider increasing the rate to 210 &#181;g/kg/min.</li>
	<li>Document FFR at stable hyperemia. An FFR reading of &#8804;0.80 is taken as significant for flow-limiting epicardial disease.</li>
	<li>With the adenosine infusion still running, switch the linked diagnostic software to complete the hyperemic thermodilution measurements.</li>
	<li>Repeat rapid 3 mL boluses of room-temperature normal saline via the guide catheter to record hyperemic thermodilution transit times.</li>
	<li>Perform the same data quality assurance checks as for the resting readings. Replace any artefactual or outlier data.</li>
	<li>Stop the IV adenosine infusion. The total duration of adenosine infusion will be approximately 2-3 minutes.</li>
	<li>Review data recordings to ensure the software-selected readings are free from artefact. Manual fine-tuning may be required. CFR &#60;2.0 (&#39;grey zone&#39; 2.0-2.5), IMR &#8805;25 and RRR &#60;2.0 are indicative of coronary microvascular dysfunction.</li>
</ol>
3. Pharmacological reactivity test
<ol>
	<li>Keep the pre-prepared acetylcholine from pharmacy at 4 &#176;C in the catheterization laboratory until use. Product shelf life is 30 hours from manufacture. The expiry date/time should be detailed on the label. Acetylcholine will be prepared at three doses: 
	Solution 1 Acetylcholine Chloride 0.182 &#181;g/mL (10-6M) 
	Solution 2 Acetylcholine Chloride 1.82 &#181;g /mL (10-5M) 
	Solution 3 Acetylcholine Chloride 18.2 &#181;g /mL (10-4M)</li>
	<li>Choose an angiographic projection that allows visualization of the coronary artery with minimal foreshortening and overlap. Acquire a resting angiogram.</li>
	<li>Check that the guide catheter is still co-axially intubated for the acetylcholine infusion. 
	NOTE: If choosing to infuse using a dedicated intracoronary microcatheter, position at this stage with the aid of a coronary guidewire. We advocate direct infusion via the guide catheter to minimize coronary instrumentation and procedural cost.</li>
	<li>Connect a long, sterile IV line to a 3-way tap and flush the system with normal saline. Connect the sterile IV line to the acetylcholine syringe which will be administered using an automated infusion pump. 
	CAUTION: Acetylcholine can temporarily interrupt cardiac conduction. Keep atropine 1 mg and alternative means of pacing available. This is more relevant for dominant coronary arteries. Coughing is effective for heart rate recovery. Inform the patient that this may be needed.</li>
	<li>Connect Solution 1 (60 mL syringe; 10-6M).
	<ol>
		<li>Purge the IV line and guide catheter with 4 mL of acetylcholine solution to minimize any &#39;dead space&#39; effect when the infusion is commenced.</li>
		<li>With the guide catheter still co-axial, commence the infusion at 2 mL/min for 2 minutes.</li>
		<li>Have the cardiac catheterization laboratory physiologist start the digital stopwatch on the monitor to ensure accurate time keeping.</li>
		<li>Monitor the patient, vital signs and ECG for effects of acetylcholine. If encountering any safety concerns, stop the acetylcholine infusion immediately.</li>
		<li>After the 2 minute infusion is complete, acquire an ECG and assess the patient for symptoms.</li>
		<li>Gently purge the guide catheter system with contrast to avoid a sudden bolus of acetylcholine with next contrast injection.</li>
		<li>Repeat the coronary angiogram in the same projection as at rest. This should be sufficiently long to assess myocardial blush and TIMI frame counts, i.e., &#62;3 heart beats.</li>
	</ol>
	</li>
	<li>Connect Solution 2 (60 mL syringe; 10-5&#160;M).
	<ol>
		<li>Purge the IV line and guide catheter with 4 mL of acetylcholine solution to minimize any &#39;dead space&#39; effect when the infusion is commenced.</li>
		<li>With the guide catheter still co-axial, commence the infusion at 2 mL/min for 2 minutes.</li>
		<li>Have the cardiac catheterization laboratory physiologist start the digital stopwatch on the monitor to ensure accurate time keeping.</li>
		<li>Monitor the patient, vital signs and ECG for effects of acetylcholine. If encountering any safety concerns, stop the acetylcholine infusion immediately.</li>
		<li>After the 2 minute infusion is complete, acquire an ECG and assess the patient for symptoms.</li>
		<li>Gently purge the guide catheter system with contrast to avoid a sudden bolus of acetylcholine with next contrast injection.</li>
		<li>Repeat the coronary angiogram in the same projection as at rest. This should be sufficiently long to assess myocardial blush and TIMI frame counts, i.e., &#62;3 heart beats.</li>
	</ol>
	</li>
	<li>Connect Solution 3 (60 mL syringe; 10-4M).
	<ol>
		<li>Purge the IV line and guide catheter with 4 mL of acetylcholine solution to minimize any &#39;dead space&#39; effect when the infusion is commenced.</li>
		<li>With the guide catheter still co-axial, commence the infusion at 2 mL/min for 2 minutes.</li>
		<li>Have the cardiac catheterization laboratory physiologist start the digital stopwatch on the monitor to ensure accurate time keeping.</li>
		<li>Monitor the patient, vital signs and ECG for effects of acetylcholine. If encountering any safety concerns, stop the acetylcholine infusion immediately.</li>
		<li>After the 2 minute infusion is complete, acquire an ECG and assess the patient for symptoms.</li>
		<li>Gently purge the guide catheter system with contrast to avoid a sudden bolus of acetylcholine with next contrast injection.</li>
		<li>Repeat the coronary angiogram in the same projection as at rest. This should be sufficiently long to assess myocardial blush and TIMI frame counts, i.e., &#62;3 heart beats.</li>
	</ol>
	</li>
	<li>Manual administration (bolus) of acetylcholine. The dose is usually 100 &#181;g (5.5 mL of Solution 3) into a left coronary artery. This should be halved if infusing into a dominant coronary artery.
	<ol>
		<li>With the guide catheter still co-axial, commence manual infusion of the desired dose over 20 seconds.</li>
		<li>Have the cardiac catheterization laboratory physiologist start the digital stopwatch on the monitor to ensure accurate time keeping.</li>
		<li>Monitor the patient, vital signs and ECG for effects of acetylcholine. If encountering any safety concerns, stop the acetylcholine infusion immediately.</li>
		<li>After the infusion is complete, acquire an ECG and assess the patient for symptoms.</li>
		<li>Gently purge the guide catheter system with contrast to avoid a sudden bolus of acetylcholine with next contrast injection.</li>
		<li>Repeat the coronary angiogram in the same projection as at rest. This should be sufficiently long to assess myocardial blush and TIMI frame counts, i.e., &#62;3 heart beats.</li>
	</ol>
	</li>
	<li>Administer 300 mcg of intracoronary GTN and allow 30 seconds to take effect.
	<ol>
		<li>Acquire an ECG and assess the patient for symptoms.</li>
		<li>Repeat the coronary angiogram in the same projection as at rest. This should be sufficiently long to assess myocardial blush and TIMI frame counts, i.e., &#62;3 heart beats.</li>
	</ol>
	</li>
	<li>Finally, perform a &#39;pullback&#39; of the diagnostic guidewire and ensure &#39;signal drift&#39; &#8804;0.03. Consider a final angiogram to exclude distal guidewire injury.</li>
</ol>
4. Multivessel assessment
<ol>
	<li>Coronary function may vary between different coronary territories. The variation reflects differences in heart muscle mass subtended by individual coronary arteries, as well as disease (e.g., fibrosis). Therefore, while the IDP is usually performed in a single coronary artery, repeat testing or investigation of additional coronary arteries may be undertaken as felt to be clinically appropriate. A typical scenario would be when the initial test results are normal despite a strong clinical history; hence, assessing a second artery would be intended to avoid a false negative result. Similarly, vasospasm may vary between coronary arteries, so multi-vessel pharmacological testing may be considered if a high index of suspicion persists despite an initial negative response.</li>
</ol>

<ol><li>Patel, M. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Low+Diagnostic+Yield+of+Elective+Coronary+Angiography%5BTitle%5D)+AND+%22Engl+J+Med%22%5BJournal%5D)">Low Diagnostic Yield of Elective Coronary Angiography.</a> Engl J Med. 362 (10), 886-895 (2010).</li>
<li>Ford, T. J., Corcoran, D., Berry, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Stable+coronary+syndromes%3A+Pathophysiology%2C+diagnostic+advances+and+therapeutic+need%5BTitle%5D)+AND+%22Heart%22%5BJournal%5D)">Stable coronary syndromes: Pathophysiology, diagnostic advances and therapeutic need.</a> Heart. 104 (4), 284-292 (2018).</li>
<li>Tavella, R., Cutri, N., Tucker, G., Adams, R., Spertus, J., Beltrame, J. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Natural+history+of+patients+with+insignificant+coronary+artery+disease%5BTitle%5D)+AND+%22European+Heart+Journal+-+Quality+of+Care+and+Clinical+Outcomes%22%5BJournal%5D)">Natural history of patients with insignificant coronary artery disease.</a> European Heart Journal - Quality of Care and Clinical Outcomes. 2 (2), 117-124 (2016).</li>
<li>Maddox, T. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Nonobstructive+coronary+artery+disease+and+risk+of+myocardial+infarction%5BTitle%5D)+AND+%22JAMA+-+Journal+of+the+American+Medical+Association%22%5BJournal%5D)">Nonobstructive coronary artery disease and risk of myocardial infarction.</a> JAMA - Journal of the American Medical Association. 312 (17), 1754-1763 (2014).</li>
<li>Jespersen, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Stable+angina+pectoris+with+no+obstructive+coronary+artery+disease+is+associated+with+increased+risks+of+major+adverse+cardiovascular+events%5BTitle%5D)+AND+%22European+Heart+Journal%22%5BJournal%5D)">Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.</a> European Heart Journal. 33 (6), 734-744 (2012).</li>
<li>Ang, D. T. Y., Berry, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((What+an+Interventionalist+Needs+to+Know+About+INOCA%5BTitle%5D)+AND+%22Interventional+Cardiology%3A+Reviews%2C+Research%2C+Resources%22%5BJournal%5D)">What an Interventionalist Needs to Know About INOCA.</a> Interventional Cardiology: Reviews, Research, Resources. 16, (2021).</li>
<li>Ong, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((International+standardization+of+diagnostic+criteria+for+microvascular+angina%5BTitle%5D)+AND+%22International+Journal+of+Cardiology%22%5BJournal%5D)">International standardization of diagnostic criteria for microvascular angina.</a> International Journal of Cardiology. 250, 16-20 (2018).</li>
<li>Neumann, F. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((ESC+Guidelines+for+the+diagnosis+and+management+of+chronic+coronary+syndromes%5BTitle%5D)+AND+%22European+Heart+Journal%22%5BJournal%5D)">ESC Guidelines for the diagnosis and management of chronic coronary syndromes.</a> European Heart Journal. 41 (3), 407-477 (2020).</li>
<li>Kunadian, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((An+EAPCI+Expert+Consensus+Document+on+Ischaemia+with+Non-Obstructive+Coronary+Arteries+in+Collaboration+with+European+Society+of+Cardiology+Working+Group+on+Coronary+Pathophysiology+%26+Microcirculation+Endorsed+by+Coronary+Vasomotor+Disorders+International%5BTitle%5D)+AND+%22European+heart+journal%22%5BJournal%5D)">An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International.</a> European heart journal. 41 (37), 3504-3520 (2020).</li>
<li>Stratified medicine methodology framework - Research - Medical Research Council. , Available from: 
 <a target="_blank" href="https://mrc.ukri.org/research/initiatives/precision-medicine/stratified-medicine-methodology-framework/">https://mrc.ukri.org/research/initiatives/precision-medicine/stratified-medicine-methodology-framework/</a> (2018).</li>
<li>Ford, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Stratified+Medical+Therapy+Using+Invasive+Coronary+Function+Testing+in+Angina%3A+The+CorMicA+Trial%5BTitle%5D)+AND+%22Journal+of+the+American+College+of+Cardiology%22%5BJournal%5D)">Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial.</a> Journal of the American College of Cardiology. 72 (23), 2841-2855 (2018).</li>
<li>Ford, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((1-Year+Outcomes+of+Angina+Management+Guided+by+Invasive+Coronary+Function+Testing+%28CorMicA%29%5BTitle%5D)+AND+%22JACC%3A+Cardiovascular+Interventions%22%5BJournal%5D)">1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA).</a> JACC: Cardiovascular Interventions. 13 (1), 33-45 (2020).</li>
<li>Williams, R. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Doppler+Versus+Thermodilution-Derived+Coronary+Microvascular+Resistance+to+Predict+Coronary+Microvascular+Dysfunction+in+Patients+With+Acute+Myocardial+Infarction+or+Stable+Angina+Pectoris%5BTitle%5D)+AND+%22The+American+Journal+of+Cardiology%22%5BJournal%5D)">Doppler Versus Thermodilution-Derived Coronary Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients With Acute Myocardial Infarction or Stable Angina Pectoris.</a> The American Journal of Cardiology. 121, 1-8 (2017).</li>
<li>Okumura, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Sensitivity+and+specificity+of+intracoronary+injection+of+acetylcholine+for+the+induction+of+coronary+artery+spasm%5BTitle%5D)+AND+%22Journal+of+the+American+College+of+Cardiology%22%5BJournal%5D)">Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.</a> Journal of the American College of Cardiology. 12 (4), 883-888 (1988).</li>
<li>Sueda, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((complications+during+spasm+provocation+tests+with+an+intracoronary+injection+of+acetylcholine%5BTitle%5D)+AND+%22The+American+journal+of+cardiology%22%5BJournal%5D)">complications during spasm provocation tests with an intracoronary injection of acetylcholine.</a> The American journal of cardiology. 85 (3), 391-394 (2000).</li>
<li>Stygall, J., Kong, R., Walker, J. M., Hardman, S. M. C., Harrison, M. J. G., Newman, S. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Cerebral+Microembolism+Detected+by+Transcranial+Doppler+During+Cardiac+Procedures%5BTitle%5D)+AND+%22Stroke%22%5BJournal%5D)">Cerebral Microembolism Detected by Transcranial Doppler During Cardiac Procedures.</a> Stroke. 31 (10), 2508-2510 (2000).</li>
<li>Ford, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Rationale+and+design+of+the+British+Heart+Foundation+%28BHF%29+Coronary+Microvascular+Angina+%28CorMicA%29+stratified+medicine+clinical+trial%5BTitle%5D)+AND+%22American+Heart+Journal%22%5BJournal%5D)">Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Angina (CorMicA) stratified medicine clinical trial.</a> American Heart Journal. 201, 86-94 (2018).</li>
<li>Sidik, N. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Rationale+and+design+of+the+British+Heart+Foundation+%28BHF%29+Coronary+Microvascular+Function+and+CT+Coronary+Angiogram+%28CorCTCA%29+study%5BTitle%5D)+AND+%22American+Heart+Journal%22%5BJournal%5D)">Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Function and CT Coronary Angiogram (CorCTCA) study.</a> American Heart Journal. 221, 48(2020).</li>
<li>Japanese Circulation Society. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Guidelines+for+diagnosis+and+treatment+of+patients+with+vasospastic+angina+%28Coronary+Spastic+Angina%29+%28JCS+2013%29%5BTitle%5D)+AND+%22Circulation+journal%3A+official+journal+of+the+Japanese+Circulation+Society%22%5BJournal%5D)">Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).</a> Circulation journal: official journal of the Japanese Circulation Society. 78 (11), 2779-2801 (2014).</li>
<li>Glyceryl Trinitrate 5 mg/ml Sterile Concentrate - Summary of Product Characteristics (SmPC) - (etc). , Available from: 
 <a target="_blank" href="https://www.medicines.org.uk/emc/product/3792/smpc#gref">https://www.medicines.org.uk/emc/product/3792/smpc#gref</a> (2022).</li>
</ol>

Drs Berry, Ang, Sidik, Morrow and Sykes are employed by the University of Glasgow which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GSK, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health.
Dr Berry receives research funding from the British Heart Foundation grant (RE/18/6134217), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1), European Union (754946-2), Medical Research Council (MR/S018905/1) and UKRI (MC/PC/20014).
Dr McEntegart has no competing interests to declare.

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 &#8804;10% (or &#8804;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.

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 &#34;follow-on&#34; 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 (&#60;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.

<table><tbody><tr><td>Coroflow software</td><td>Coroventis</td><td>N/A</td><td>https://www.coroventis.com/coroflow/measurements-indepth/</td></tr><tr><td>Miochol-E, 20 mg, Powder and Solvent for instillation solution for intraocular use.</td><td>Bausch &amp;amp; Lomb U.K Limited</td><td>Unlicensed for parenteral use</td><td>https://www.medicines.org.uk/emc/product/4795/smpc#gref</td></tr><tr><td>PressureWire Receiver</td><td>Abbott Vascular</td><td>C17040</td><td>https://www.cardiovascular.abbott/us/en/hcp/products/percutaneous-coronary-intervention/pressurewireX-guidewires-physiology/ht-tab/ordering-info.html</td></tr><tr><td>PressureWire X Guidewire, 175 cm</td><td>Abbott Vascular</td><td>C12059</td><td>https://www.cardiovascular.abbott/us/en/hcp/products/percutaneous-coronary-intervention/pressurewireX-guidewires-physiology/ht-tab/ordering-info.html</td></tr></tbody></table>

interventional diagnostic procedure: a practical guide for the assessment of coronary vascular function

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.

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 &#8804;0.80 is indicative of obstructive epicardial disease.
CFR &#60;2.0 (2.0-2.5 = &#39;grey zone&#39;) in the absence of obstructive epicardial disease is indicative of microvascular angina.
IMR &#8805;25 is indicative of microvascular angina.
RRR&#60;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 &#8805;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, &#60;90% change in epicardial lumen diameter, and/or TIMI flow reduction.
Table 1: Diagnostic criteria for each endotype (disease sub-group). <a href="https://www.jove.com/files/ftp_upload/62265/Table1.xlsx" target="_blank">Please click here to download this Table.</a>
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/62265/62265fig01.jpg" /> 
Figure 1: Summary flow-chart for interpretation of IDP results, with illustrative examples. IMR, index of microvascular resistance; CFR, coronary flow reserve. <a href="https://www.jove.com/files/ftp_upload/62265/62265fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function at JoVE.com

Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function

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 ...

interventional-diagnostic-procedure-practical-guide-for-assessment

Research

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Medicine

4.8K Views.  Golden Jubilee National Hospital. Veel patiënten met angina pectoris hebben geen obstructieve coronaire hartziekte op het moment van angiografie. Dit wordt ook wel INOCA genoemd. Hier presenteren we een uitgebreid gouden standaardprotocol voor het testen van structurele en functionele stoornissen van de coronaire circulatie.Deze techniek bestaat uit twee componenten, de diagnostische guidewire-studie en de acetylcholine-provocatietest. Samen bieden ze aanvullende informatie om onderscheid te maken tussen de INOCA-endy...

Video: Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function

Assessing Endothelial Vasodilator Function with the Endo-PAT 2000

The endothelium is a delicate monolayer of cells that lines all blood vessels, and which comprises the systemic and lymphatic capillaries. By virtue of the panoply of paracrine factors that it secretes, the endothelium regulates the contractile and proliferative state of the underlying vascular smooth muscle, as well as the interaction of the vessel wall with circulating blood elements. Because of its central role in mediating vessel tone and growth, its position as gateway to circulating immune cells, and its local regulation of hemostasis and coagulation, the the properly functioning endothelium is the key to cardiovascular health. Conversely, the earliest disorder in most vascular diseases is endothelial dysfunction.
In the arterial circulation, the healthy endothelium generally exerts a vasodilator influence on the vascular smooth muscle. There are a number of methods to assess endothelial vasodilator function. The Endo-PAT 2000 is a new device that is used to assess endothelial vasodilator function in a rapid and non-invasive fashion. Unlike the commonly used technique of duplex ultra-sonography to assess flow-mediated vasodilation, it is totally non-operator-dependent, and the equipment is an order of magnitude less expensive. The device records endothelium-mediated changes in the digital pulse waveform known as the PAT ( peripheral Arterial Tone) signal, measured with a pair of novel modified plethysmographic probes situated on the finger index of each hand. Endothelium-mediated changes in the PAT signal are elicited by creating a downstream hyperemic response. Hyperemia is induced by occluding blood flow through the brachial artery for 5 minutes using an inflatable cuff on one hand. The response to reactive hyperemia is calculated automatically by the system. A PAT ratio is created using the post and pre occlusion values. These values are normalized to measurements from the contra-lateral arm, which serves as control for non-endothelial dependent systemic effects. Most notably, this normalization controls for fluctuations in sympathetic nerve outflow that may induce changes in peripheral arterial tone that are superimposed on the hyperemic response.
In this video we demonstrate how to use the Endo-PAT 2000 to perform a clinically relevant assessment of endothelial vasodilator function.

A noninvasive procedure to assess endothelial function is demonstrated using the Endo-PAT 2000.

The endothelium is a delicate monolayer of cells that lines all blood vessels, and which comprises the systemic and lymphatic capillaries. By virtue of ...

A Methodological Approach to Non-invasive Assessments of Vascular Function and Morphology

The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis. Damage to the endothelium may predispose the vessel to atherosclerosis and increase the risk for cardiovascular disease. Assessments of peripheral endothelial function are good indicators of early abnormalities in the vascular wall and correlate well with assessments of coronary endothelial function. The present manuscript details the important methodological steps necessary for the assessment of microvascular endothelial function using laser Doppler imaging with iontophoresis, large vessel endothelial function using flow-mediated dilatation, and carotid atherosclerosis using carotid artery ultrasound. A discussion on the methodological considerations for each of the techniques is also presented, and recommendations are made for future research.

The present article describes the methodological considerations for several non-invasive assessments of vascular function and morphology that are commonly used in medical research to assess different stages of atherosclerosis.

The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis.  Damage to the endothelium may ...

 IVUS-Based Computational Method to Quantify Coronary Mechanical Properties

Intravascular Ultrasound Image-Based Finite Element Modeling Approach for Quantifying In Vivo Mechanical Properties of Human Coronary Artery

Quantifying the mechanical properties of coronary arterial walls could provide meaningful information for the diagnosis, management, and treatment of coronary artery diseases. Since patient-specific coronary samples are not available for patients requiring continuous monitoring, direct experimental testing of vessel material properties becomes impossible. Current coronary models typically use material parameters from available literature, leading to significant mechanical stress/strain calculation errors. Here, we would introduce a finite element model-based updating approach (FEMBUA) to quantify patient-specific in vivo material properties of coronary arteries based on medical images. In vivo cine intravascular ultrasound (IVUS) and virtual histology (VH)-IVUS images of coronary arteries were acquired from a patient with coronary artery disease. Cine IVUS images showing the vascular movement over one cardiac cycle were segmented, and two IVUS frames with maximum and minimum lumen circumferences were selected to represent the coronary geometry under systolic and diastolic pressure conditions, respectively. VH-IVUS image was also segmented to obtain the vessel contours, and a layer thickness of 0.05 cm was added to the VH-IVUS contours to reconstruct the coronary geometry. A computational finite element model was created with an anisotropic Mooney-Rivlin material model used to describe the vessel's mechanical properties and pulsatile blood pressure conditions prescribed to the coronary luminal surface to make it contract and expand. Then, an iterative updating approach was employed to determine the material parameters of the anisotropic Mooney-Rivlin model by matching minimum and maximum lumen circumferences from the computational finite element model with those from cine IVUS images. This image-based finite element model-based updating approach could be successfully extended to determine the material properties of arterial walls in various vascular beds and holds the potential for risk assessment of cardiovascular diseases.

In vivo cine intravascular ultrasound images show the coronary cross-sectional movement corresponding to different pressure loading conditions. Based on a finite element model, an iterative scheme was employed to determine the patient-specific mechanical properties of coronary arteries in vivo by matching coronary motion from the computational model and medical images.

Quantifying the mechanical properties of coronary arterial walls could provide meaningful information for the diagnosis, management, and treatment of ...

Engineering

Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders

Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the catheterization laboratory which was introduced more than 30 years ago. Due to the short half-life of acetylcholine it can only be applied directly into the coronary arteries. Several studies have demonstrated the safety and clinical usefulness of this test. However, acetylcholine testing is only rarely applied in the U.S. or Europe. Nevertheless, it has been shown that 62% of Caucasian patients with stable angina and unobstructed coronary arteries on coronary angiography suffer from coronary vasomotor disorders that can be diagnosed with acetylcholine testing. In recent years it has been appreciated that the ACH-test not only assesses the presence of epicardial spasm but that it can also be useful for the detection of coronary microvascular spam. In such cases no epicardial spasm is seen after injection of acetylcholine but ischemic ECG shifts are present together with a reproduction of the patient's symptoms during the test. This article describes the experience with the ACH-test and its implementation in daily clinical routine.

Intracoronary acetylcholine testing has been established for the assessment of epicardial coronary spasm more than 30 years ago. Recently, the focus has shifted towards the microcirculation and it has been shown that microvascular spasm can be detected using ACH-testing. This article describes the ACH-test and its implementation in daily routine.

Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the ...

Evaluation of Coronary Flow Reserve After Myocardial Ischemia Reperfusion in Rats

Coronary artery disease is the leading cause of death worldwide. After an acute myocardial infarction, early and successful myocardial intervention via recanalization of the coronary artery is the most effective strategy for reducing the size of ischemic myocardium. The coronary microvasculature cannot be visualized and imaged&#160;in vivo, but there are several invasive and noninvasive techniques that can be used to assess parameters which depend directly on coronary microvascular function. The endothelial function after ischemia reperfusion can be assessed also at the level of the coronary circulation via the coronary flow reserve (CFR).&#160;In this study, peak velocity of left anterior descending (LAD) coronary arteries was measured in rats in vivo via Transthoracic Doppler Echocardiography during resting and stress challenge (induced by Dobutamine). A normal heart can increase its coronary blood flow up to four times above the resting values during stress induction. Following ischemia reperfusion, we found a significantly diminished CFR, which can be used as a marker of coronary microvascular dysfunction. CFR has opened a window on the importance of microvascular dysfunction and has been shown to predict cardiovascular risk independent of whether the severe obstructive disease is present.

Coronary flow reserve (CFR), is defined as the ratio of maximal coronary blood flow to the resting coronary blood flow. We present a protocol for evaluating CFR in rats via ultrasound, which offers the opportunity to predict cardiovascular risk factors in the absence of obstructive coronary disease.

Coronary artery disease is the leading cause of death worldwide. After an acute myocardial infarction, early and successful myocardial intervention via ...

Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in G&#246;ttingen Minipigs and Landrace Pigs

The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an unmet clinical need for prevention and therapy of post-myocardial infarction heart failure (post-MI HF). Clinically relevant pig models of post-MI HF are prerequisites for final proof-of-concept studies before entering into clinical trials in drug and medical device development.
Here we aimed to characterize a closed-chest porcine model of post-MI HF in adult G&#246;ttingen minipigs with long-term follow-up including serial cardiac magnetic resonance imaging (CMRI) and to compare it with the commonly used Landrace pig model.
MI was induced by intraluminal balloon occlusion of the left anterior descending coronary artery for 120 min in G&#246;ttingen minipigs and for 90 min in Landrace pigs, followed by reperfusion. CMRI was performed to assess cardiac morphology and function at baseline in both breeds and at 3 and 6 months in G&#246;ttingen minipigs and at 2 months in Landrace pigs, respectively.
Scar sizes were comparable in the two breeds, but MI resulted in a significant decrease of left ventricular ejection fraction (LVEF) only in G&#246;ttingen minipigs, while Landrace pigs did not show a reduction of LVEF. Right ventricular (RV) ejection fraction increased in both breeds despite the negligible RV scar sizes. In contrast to the significant increase of left ventricular end-diastolic (LVED) mass in Landrace pigs at 2 months, G&#246;ttingen minipigs showed a slight increase in LVED mass only at 6 months.
In summary, this is the first characterization of post-MI HF in G&#246;ttingen minipigs in comparison to Landrace pigs, showing that the G&#246;ttingen minipig model reflects post-MI HF parameters comparable to the human pathology. We conclude that the G&#246;ttingen minipig model is superior to the Landrace pig model to study the development of post-MI HF.

The overall goal of the current study is to present the techniques of induction of myocardial infarction (MI) and post-myocardial infarction heart failure (post-MI HF) in closed-chest, adult G&#246;ttingen minipigs and the characterization of post-MI HF model in G&#246;ttingen minipigs as compared to Landrace pigs.

The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an ...

Quantification of Absolute Myocardial Flow and Resistance by Continuous Thermodilution in Patients with Ischemia and Nonobstructive Coronary Artery Disease (INOCA)

In approximately half of the patients undergoing coronary angiography for angina pectoris or for signs or symptoms suggestive of ischemic heart disease, no obstructive coronary artery disease is angiographically visible. The majority of these patients with angina or ischemia and no obstructive coronary artery disease (INOCA) have an underlying coronary vasomotor dysfunction, and current consensus documents recommend diagnostic invasive coronary vasomotor function testing (CFT). 
During CFT, a variety of vasomotor dysfunction endotypes can be assessed, including vasospastic coronary dysfunction (epicardial or microvascular vasospasm), and/or microvascular vasodilatory dysfunction, including impaired vasodilatory capacity and increased microvascular resistance. The quantification of the continuous thermodilution derived absolute coronary blood flow and resistance might be a better measure compared to the currently used standard physiologic measures. This article provides an overview of this continuous thermodilution method.

Quantification of Absolute Myocardial Flow and Resistance by Continuous Thermodilution in Patients with Ischemia and Nonobstructive Coronary Artery Disease INOCA

Presented here is a protocol to measure absolute myocardial flow and resistance using continuous thermodilution in patients with ischemia and nonobstructive coronary artery disease.

In approximately half of the patients undergoing coronary angiography for angina pectoris or for signs or symptoms suggestive of ischemic heart disease, ...

Testing Acetylcholine Followed by Adenosine for Invasive Diagnosis of Coronary Vasomotor Disorders

More than 50% of patients with signs and symptoms of myocardial ischemia undergoing coronary angiography have unobstructed coronary arteries. Coronary vasomotor disorders (impaired vasodilatation and/or enhanced vasoconstriction/spasm) represent important functional causes for such a clinical presentation. Although impaired vasodilatation may be assessed with non-invasive techniques such as positron emission tomography or cardiac magnetic resonance imaging, there is currently no reliable non-invasive technique for the diagnosis of coronary spasm available. Thus, invasive diagnostic procedures (IDP) have been developed for the diagnosis of coronary vasomotor disorders including spasm testing as well as assessment of coronary vasodilatation. The identification of the underlying type of disorder (so called endotype) allows the initiation of targeted pharmacological treatments. Despite the fact that such an approach is recommended by the current European Society of Cardiology guidelines for the management of chronic coronary syndromes based on the CorMicA study, comparability of results as well as multicenter trials are currently hampered by major differences in institutional protocols for coronary functional testing. This article describes a comprehensive IDP protocol including intracoronary acetylcholine provocation testing for diagnosis of epicardial/microvascular spasm, followed by Doppler wire-based assessment of coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) in search of coronary vasodilatory impairment.

Coronary vasomotion disorders represent frequent functional causes of angina in patients with unobstructed coronaries. The underlying mechanism of angina (endotype) in these patients can be determined by a comprehensive invasive diagnostic procedure based on acetylcholine provocation testing followed by Doppler-derived assessment of the coronary flow reserve and microvascular resistance.

More than 50% of patients with signs and symptoms of myocardial ischemia undergoing coronary angiography have unobstructed coronary arteries. Coronary ...

Preclinical Evaluation of Coronary Artery Stents

Coronary artery disease is a major contributor to morbidity and mortality worldwide. While lifestyle changes and medication are the cornerstones of treatment, coronary artery balloon angioplasty and stenting are routinely performed on patients with acute coronary syndromes and chronic coronary artery disease who remain symptomatic with optical medical treatment. Several generations of coronary stents have been developed over recent decades. Balloon angioplasty and stenting are supported by the use of pharmaceutical agents applied onto balloons and the stent surface, either to advance the healing properties of the artery post-intervention or to prevent the formation of restenosis. New devices need to be rigorously tested for safety and efficacy before acceptance into clinical practice; thus, there is a continuing need for reliable and reproducible preclinical methods of stent evaluation. We describe here a pig coronary artery model as well as an atherosclerotic rabbit model for coronary artery stent research and describe basic steps in intravascular imaging and stent histology.

New coronary artery stent designs and materials must be tested before clinical use in relevant preclinical models. Here we describe an atherosclerotic rabbit aorta model and a pig coronary artery model for stent research with in vivo and histological analyses.

Coronary artery disease is a major contributor to morbidity and mortality worldwide. While lifestyle changes and medication are the cornerstones of ...

Non-Invasive Point-of-Care Test for Coronary Artery Disease Assessment 

Signal Acquisition, Score Interpretation, and Economics of a Non-Invasive Point-of-Care Test for Coronary Artery Disease

A point-of-care non-invasive test for Coronary Artery Disease (CAD) (POC-CAD) has been previously developed and validated. The test requires the simultaneous acquisition of orthogonal voltage gradient (OVG) and photoplethysmogram signals, which is the primary methodology described in this paper. The acquisition of the OVG, a biopotential signal, necessitates the placement of electrodes on the prepared skin of the patient&#39;s thorax (arranged similarly to the Frank lead configuration, comprising six bipolar electrodes and a reference electrode) and a hemodynamic sensor on the finger (using a standard transmission modality). The signal is uploaded to a cloud-based system, where engineered features are extracted from the signal and supplied to a machine-learned algorithm to yield the CAD Score. The physician must then interpret the value of the CAD Score in the context of their patient&#39;s pre-test probability of CAD, resulting in a post-test probability of CAD. This interpretation can be performed at the level of test positivity and test negativity or at a finer level of granularity; methodologies for each are proposed here based on likelihood ratios. Using the post-test probability, the physician must determine the appropriate next step in the treatment of their patient; several scenarios are used to illustrate this process. Test adoption is only feasible if economically viable; a discussion of the integration of the test into the CAD diagnostic flow and the resultant cost savings to the healthcare system is provided. The economic model demonstrates that cost savings to the healthcare system can be achieved by preventing delayed treatment, which, if left unaddressed, results in disease progression requiring more advanced (and expensive) care.

The methodology to acquire the physiological signal for a Coronary Artery Disease (CAD) test is presented. A method is proposed to interpret the CAD score concerning test positivity and negativity, including the granularities of each. The economics of the test are discussed in the context of the current standard of care.

Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function

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