Name: testing acetylcholine followed by adenosine for invasive diagnosis of coronary vasomotor disorders
Uploaded: 2021-02-03T14:30:00
Description: Watch this Scientific Journal Video about Testing Acetylcholine Followed by Adenosine for Invasive Diagnosis of Coronary Vasomotor Disorders at JoVE.com

This project was supported by the Berthold-Leibinger-Foundation, Ditzingen, Germany.

Intracoronary ACh testing has been approved by the local ethics committee and the protocol follows the guidelines of our institution for human research. A previous JoVE article covered a protocol showing preparation of the ACh solutions as well as preparation of the syringes for intracoronary injection of ACh15.
1. Preparation of the ACh solutions and preparation of the syringes for intracoronary injection of ACh
<ol>
	<li>Please refer to a previously published JoVE a...

<ol>
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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ischemia+and+No+Obstructive+Coronary+Artery+Disease:+Prevalence+and+Correlates+of+Coronary+Vasomotion+Disorders.">Ischemia and No Obstructive Coronary Artery Disease: Prevalence and Correlates of Coronary Vasomotion Disorders.</a> Circulation. Cardiovascular Interventions. 12 (12), 008126 (2019).</li><li>Suda, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coronary+Functional+Abnormalities+in+Patients+With+Angina+and+Nonobstructive+Coronary+Artery+Disease.">Coronary Functional Abnormalities in Patients With Angina and Nonobstructive Coronary Artery Disease.</a> Journal of the American College of Cardiology. 74 (19), 2350-2360 (2019).</li><li>Ford, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stratified+Medical+Therapy+Using+Invasive+Coronary+Function+Testing+in+Angina:+The+CorMicA+Trial.">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>Ong, P., Athanasiadis, A., Sechtem, U. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intracoronary+Acetylcholine+Provocation+Testing+for+Assessment+of+Coronary+Vasomotor+Disorders.">Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders.</a> Journal of Visualized Experiments. (114), (2016).</li><li>Sara, J. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prevalence+of+Coronary+Microvascular+Dysfunction+Among+Patients+With+Chest+Pain+and+Nonobstructive+Coronary+Artery+Disease.">Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease.</a> JACC. Cardiovascular Interventions. 8 (11), 1445-1453 (2015).</li><li>Kunadian, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&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+&amp;+Microcirculation+Endorsed+by+Coronary+Vasomotor+Disorders+International+Study+Group.">An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology &amp; Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.</a> European Heart Journal. 41 (37), 3504-3520 (2020).</li><li>Ong, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High+prevalence+of+a+pathological+response+to+acetylcholine+testing+in+patients+with+stable+angina+pectoris+and+unobstructed+coronary+arteries.+The+ACOVA+Study+(Abnormal+COronary+VAsomotion+in+patients+with+stable+angina+and+unobstructed+coronary+arteries.">High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries.</a> Journal of the American College of Cardiology. 59 (7), 655-662 (2012).</li><li>Mohri, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Angina+pectoris+caused+by+coronary+microvascular+spasm.">Angina pectoris caused by coronary microvascular spasm.</a> The Lancet. 351 (9110), 1165-1169 (1998).</li><li>Sun, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coronary+microvascular+spasm+causes+myocardial+ischemia+in+patients+with+vasospastic+angina.">Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina.</a> Journal of the American College of Cardiology. 39 (5), 847-851 (2002).</li><li>Waxman, S., Moreno, R., Rowe, K. A., Verrier, R. 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Management of patients with angina and unobstructed coronary arteries is often demanding and sometimes frustrating. An important step during the work-up of these patients is that the underlying pathophysiological mechanism(s) for the patient&#39;s symptoms are adequately investigated. This is challenging as often not only one mechanism is responsible and various aetiologies including cardiac and non-cardiac as well as coronary and non-coronary need to be taken into account.
Frequently patients...

In recent years interventional cardiology has made substantial progress in various areas. This not only comprises interventional treatment of the heart valves using transcatheter aortic valve replacement and edge-to-edge repair of the mitral and tricuspid valve, but also coronary interventions1,2,3,4,5,6. Among the latter are advances in techniques for treatment of chronic total occlusions as well as calcified lesions using rotablation and shock wave therapy. In addition to these rather structural coronary interventional procedures invasive diagnostic procedures (IDP) have now been established in search of functional coronary disorders (i.e., coronary spasm and microvascular dysfunction)7. The latter comprise a heterogeneous group of conditions frequently but not exclusively occurring in patients with angina pectoris and unobstructed coronary arteries. The main mechanisms underlying these vasomotor disorders are impaired coronary vasodilatation, enhanced vasoconstriction/spasm as well as enhanced coronary microvascular resistance. The latter is often due to obstructive microvascular disease8. Anatomically, coronary vasomotor disorders may occur in the epicardial arteries, the coronary microcirculation or both. The Coronary Vasomotor Disorders International Study group (COVADIS) has published definitions for the diagnosis of these disorders9,10 and recent guidelines of the European Society of Cardiology (ESC) on the management of patients with chronic coronary syndrome have made recommendations for adequate patient assessment depending on the clinical condition11. Moreover, recent publications have delineated the various endotypes that can be derived from an IDP12,13. Such an approach has a benefit for the individual patient as randomized studies have shown better quality of life in patients undergoing an IDP followed by stratified medical therapy according to the test result compared to usual care by the general practitioner14. Currently, there is a debate about the most appropriate protocol for testing of such vasomotor disorders. The aim of this article is to describe a protocol where acetylcholine (ACh) provocation testing in search of coronary spasm is followed by Doppler wire-based assessment of coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) using adenosine (Figure 1).

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Cannula 0,95 x 50 mm (arterial punction)</td>
			<td>BBraun</td>
			<td>4206096</td>
			<td></td>
		</tr>
		<tr>
			<td>Cannula 23 G 0,6 x 25 mm (local anesthesia)</td>
			<td>BBraun</td>
			<td>4670025S-01</td>
			<td></td>
		</tr>
		<tr>
			<td>Coronary angiography suite (AXIOM Artis MP eco)</td>
			<td>Siemens</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>Contrast agent Imeron 350 with a 10 mL syringe for contrast injection</td>
			<td>Bracco Imaging</td>
			<td>30699.04.00</td>
			<td></td>
		</tr>
		<tr>
			<td>Diagnostic catheter (various manufacturers)</td>
			<td>e.g. Medtronic</td>
			<td>DXT5JR40</td>
			<td></td>
		</tr>
		<tr>
			<td>Glidesheath Slender 6 Fr</td>
			<td>Terumo</td>
			<td>RM*RS6J10PQ</td>
			<td></td>
		</tr>
		<tr>
			<td>Heparin 5,000 IU (25,000 IU / 5 mL)</td>
			<td>BBraun</td>
			<td>1708.00.00</td>
			<td></td>
		</tr>
		<tr>
			<td>Mepivacaine 10 mg/mL</td>
			<td>PUREN Pharma</td>
			<td>11356266</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium chloride solution 0.9 % (1 x 100 mL)</td>
			<td>BBraun</td>
			<td>32000950</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 2 mL (1x) (local anesthesia)</td>
			<td>BBraun</td>
			<td>4606027V</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 10 mL (1x) (Heparin)</td>
			<td>BBraun</td>
			<td>4606108V</td>
			<td></td>
		</tr>
		<tr>
			<td>Acetylcholine chloride (vial of 20 mg acetylcholine chloride powder and 1 ampoule of 2 mL diluent)</td>
			<td>Bausch &#38; Lomb</td>
			<td>NDC 240208-539-20</td>
			<td></td>
		</tr>
		<tr>
			<td>Cannula 20 G 70 mm (2x)</td>
			<td>BBraun</td>
			<td>4665791</td>
			<td></td>
		</tr>
		<tr>
			<td>Glyceryle Trinitrate 1 mg/mL (5 mL)</td>
			<td>Pohl-Boskamp</td>
			<td>07242798</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium chloride solution 0.9 % (3 x 100 mL)</td>
			<td>BBraun</td>
			<td>32000950</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 2 mL (1x)</td>
			<td>BBraun</td>
			<td>4606027V</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 5 mL (5x)</td>
			<td>BBraun</td>
			<td>4606051V</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 10 mL (1x)</td>
			<td>BBraun</td>
			<td>4606108V</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 50 mL (3x)</td>
			<td>BBraun</td>
			<td>4187903</td>
			<td></td>
		</tr>
		<tr>
			<td>Adenosine 6 mg/2 mL</td>
			<td>Sanofi-Aventis</td>
			<td>30124.00.00</td>
			<td></td>
		</tr>
		<tr>
			<td>ComboMap Pressure/Flow System</td>
			<td>Volcano</td>
			<td>Model No. 6800 (Powers Up)</td>
			<td></td>
		</tr>
		<tr>
			<td>Pressure/Flow Guide Wire</td>
			<td>Volcano</td>
			<td>9515</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium chloride solution 0.9 % (1 x 100 mL)</td>
			<td>BBraun</td>
			<td>32000950</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe 10 mL (3x)</td>
			<td>BBraun</td>
			<td>4606108V</td>
			<td></td>
		</tr>
	</tbody>
</table>

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.

According to the diagnostic criteria suggested by COVADIS9, vasospastic angina can be diagnosed if the following criteria apply during ACh provocation testing: transient ECG changes indicating ischemia, reproduction of the patient&#180;s usual anginal symptoms and &#62; 90% vasoconstriction of an epicardial vessel&#160;as confirmed during coronary angiography (Figure 2).
Spas...

Watch this Scientific Journal Video about Testing Acetylcholine Followed by Adenosine for Invasive Diagnosis of Coronary Vasomotor Disorders at JoVE.com

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

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 ...

The invasive diagnostic procedure, the so-called IDP, allows to identify functional coronary diseases, which are frequent mechanisms of angina in patients with unobstructed coronary arteries. The IDP provides a comprehensive evaluation of the dilatory and constrictive component of coronary vasomotion using intracoronary flow and pressure measurements. This is done at rest and during hyperemia, and also coronary spasm testing is performed.There are different subtypes of functional coronary diseases, which are associated with different prognosis and treatment recommendations. The IDP helps to make the diagnosis and to find the optimal treatment. Begin by placing a guiding catheter suitable for the left coronary artery into the left main artery, and deliver another 5, 000 international units of heparin.Advance the Doppler flow pressure wire through the guiding catheter into the left main artery, and after flushing to avoid any contrast in the catheter, calibrate the distal pressure sensor of the Doppler flow pressure wire. Place the tip of the wire in the proximal mid portion of the vessel, usually the left anterior descending artery, and perform thoracoscopy to record the wire position. Press record to record the signals on the system and assess and optimize the Doppler in ECG signal quality as necessary.Once the recording has been started, inject six milliliters of the lowest acetylcholine concentration into the left coronary artery over a period of 20 seconds. Afterwards, flush the catheter with three to four milliliters of saline while performing continuous monitoring of the patient's symptoms, the 12-lead ECG, and the coronary blood flow velocity. Next, perform coronary angiography by injecting 10 milliliters of contrast agent through the catheter.After one minute, inject six milliliters of the medium acetylcholine concentration before flushing with three to four milliliters of saline and recording the average peak velocity, the 12-lead ECG, and the patient's symptoms as demonstrated. Perform coronary and geography of the left coronary artery as previously demonstrated, and if no spasm occurs, continue with injecting 5.5 milliliters of the highest acetylcholine concentration, followed by three to four milliliters of saline. If no epicardial spasm occurs at the 100 microgram dose, continue with the 200 microgram dose while continuously monitoring the ECG and the patient symptoms.When symptoms, ischemic ECG shifts, or epicardial spasm occurs, inject 200 micrograms of nitroglycerin and perform coronary angiography after one minute to document the reversion of the spasm. After the average peak velocity has returned to baseline and the patient's symptoms have returned to normal, press Base to capture the baseline values of the average peak velocity. Quickly inject a bolus of 3.5 milliliters of adenosine solution followed by a brief 10 milliliter saline flush.Press the Peak Search button three heartbeats after the injection to initiate a peak search. The system will calculate and display the values for fractional flow reserve, coronary flow reserve, and hyperemic microvascular resistance. Repeat for at least two consistent measurements, then retract the wire and obtain a final angiogram to exclude any vessel injury.According to the diagnostic criteria epicardial spasm can be diagnosed if transient ECG changes indicating ischemia, reproduction of the patient's usual anginal symptoms, and at least 90%vasoconstriction of an epicardial vessel as confirmed during coronary angiography can be observed. Spasm of the coronary microvasculature can be diagnosed if the patient's symptoms and ischemic ECG alterations occurred during provocation testing in the absence of epicardial vasospasm. Impaired microvascular vasodilation can be diagnosed by interpreting the CFR and HMR measurements following adenosine injections.Depending on the cutoff values applied, a reduced CFR is defined as less than 2.0 or 2.5 or less. For HMR, data on the optimal cutoff values is scarce, but an increased microvascular resistance is currently defined as an HMR greater than 1.9 or greater than 2.4. In order to obtain an informative IDP, it is very important to ensure the quality of the Dopplar signal is appropriate and also to ensure that the 12-lead ECG during acetylcholine testing is interpretable.This is required for an optimal IDP. The IDP can be expanded by additional tests such as the acetylcholine re-challenge after anti-vasospastic drug administration in order to evaluate its efficacy in the individual patient.

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