Name: acetylcholine re-challenge after intracoronary nitroglycerine administration
Uploaded: 2022-04-04T13:00:00
Description: Watch this Scientific Journal Video about Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration at JoVE.com

Intracoronary ACh testing has been approved by the local ethics committee of the Academic Medical Centre, and the protocol follows the guidelines of Amsterdam UMC for human research.
1. Preparation of the ACh stock solution
<ol>
	<li>Mix the 20 mg of ACh with the 2 mL of solvent provided with the package (Table of Materials).</li>
	<li>Add 1 mL of the ACh solution to 499 mL of 0.9% NaCl to create the stock solution, corresponding to a 20 &#181;g/mL dose.</li...

<ol>
	<li>Knuuti, 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=2019+ESC+Guidelines+for+the+diagnosis+and+management+of+chronic+coronary+syndromes.">2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.</a> European Heart Journal. 41 (3), 407-477 (2020).</li><li>JCS Joint Working Group. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Guidelines+for+diagnosis+and+treatment+of+patients+with+vasospastic+angina+(Coronary+Spastic+Angina)+(JCS+2013).">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>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=International+standardization+of+diagnostic+criteria+for+microvascular+angina.">International standardization of diagnostic criteria for microvascular angina.</a> International Journal of Cardiology. 250, 16-20 (2018).</li><li>Beltrame, J. F., 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=International+standardization+of+diagnostic+criteria+for+vasospastic+angina.">International standardization of diagnostic criteria for vasospastic angina.</a> European Heart Journal. 38 (33), 2565-2568 (2017).</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=1-Year+Outcomes+of+angina+management+guided+by+invasive+coronary+function+testing+(CorMicA).">1-Year Outcomes of angina management guided by invasive coronary function testing (CorMicA).</a> JACC: Cardiovascular Interventions. 13 (1), 33-45 (2020).</li><li>Bairey Merz, C. N., Pepine, C. J., Walsh, M. N., Fleg, J. L. <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+(INOCA):+Developing+evidence-based+therapies+and+research+agenda+for+the+next+decade.">Ischemia and no obstructive coronary artery disease (INOCA): Developing evidence-based therapies and research agenda for the next decade.</a> Circulation. 135 (11), 1075-1092 (2017).</li><li>Sun, H., Fukumoto, Y., Ito, A., Shimokawa, H., Sunagawa, K. <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+dysfunction+in+patients+with+microvascular+angina:+analysis+by+TIMI+frame+count.">Coronary microvascular dysfunction in patients with microvascular angina: analysis by TIMI frame count.</a> Journal of Cardiovascular Pharmacology. 46 (5), 622-626 (2005).</li><li>Kiyooka, T., Kobayashi, Y., Ikari, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+case+of+vasospastic+angina+in+which+the+ergonovine+provocation+test+with+intracoronary+isosorbide+dinitrate+and+nicorandil+was+effective+in+the+diagnosis+of+microvascular+spasm.">A case of vasospastic angina in which the ergonovine provocation test with intracoronary isosorbide dinitrate and nicorandil was effective in the diagnosis of microvascular spasm.</a> Cardiovascular Intervention and Therapeutics. 29 (4), 344-349 (2014).</li><li>Takahashi, 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=Prognostic+impact+of+chronic+nitrate+therapy+in+patients+with+vasospastic+angina:+multicentre+registry+study+of+the+Japanese+coronary+spasm+association.">Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.</a> European Heart Journal. 36 (4), 228-237 (2015).</li><li>Ferrari, R., 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=Expert+consensus+document:+A+'diamond'+approach+to+personalized+treatment+of+angina.">Expert consensus document: A 'diamond' approach to personalized treatment of angina.</a> Nature Reviews Cardiology. 15 (2), 120-132 (2018).</li><li>Redfield, M. 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=Isosorbide+mononitrate+in+heart+failure+with+preserved+ejection+fraction.">Isosorbide mononitrate in heart failure with preserved ejection fraction.</a> The New England Journal of Medicine. 373 (24), 2314-2324 (2015).</li><li>Seitz, 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=Acetylcholine+rechallenge:+A+first+step+towards+tailored+treatment+in+patients+with+coronary+artery+spasm.">Acetylcholine rechallenge: A first step towards tailored treatment in patients with coronary artery spasm.</a> Journal of the American College of Cardiology: Cardiovascular Interventions. 15 (1), 65-75 (2022).</li><li>Crea, F., Lanza, G. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+microvascular+angina:+The+need+for+precision+medicine.">Treatment of microvascular angina: The need for precision medicine.</a> European Heart Journal. 37 (19), 1514-1516 (2016).</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: JoVE. (114), e54295 (2016).</li><li>Han, S. 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=Impact+of+multi-vessel+vasospastic+angina+on+cardiovascular+outcome.">Impact of multi-vessel vasospastic angina on cardiovascular outcome.</a> Atherosclerosis. 281, 107-113 (2019).</li><li>Feenstra, R. G. T., 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=Principles+and+pitfalls+in+coronary+vasomotor+function+testing.">Principles and pitfalls in coronary vasomotor function testing.</a> EuroIntervention: Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. , (2021).</li><li>Seitz, A., Beck, S., Pereyra, V. M., Bekeredjian, R., Sechtem, U., Ong, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Testing+acetylcholine+followed+by+adenosine+for+invasive+diagnosis+of+coronary+vasomotor+disorders.">Testing acetylcholine followed by adenosine for invasive diagnosis of coronary vasomotor disorders.</a> Journal of Visualized Experiments: JoVE. (168), e62134 (2021).</li></ol>

The usefulness of the ACh after NTG rechallenge has shown to be two-fold: (1) to unmask the co-existence of microvascular spasm in patients with epicardial spasm and (2) to assess the preventive efficacy of NTG on a per-patient level in order to guide medical therapy12. Regardless of the result of the spasm provocation test, intracoronary NTG is always routinely administered into the target vessel after the test or when severe symptoms, ischemic ECG changes, or epicardial spasm&#160;occur. Adding ...

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina and non-obstructive coronary artery disease (ANOCA) by means of spasm provocation testing with acetylcholine(ACh)1,2,3,4.The recent CorMicA trial demonstrated that identification and concurrent tailored treatment of CAS persistently improve the patient&#39;s quality of life and reduce the burden of angina5. Usually, once CAS is diagnosed, it is regarded as one distinct disease and treated with anti-vasospastic medication, such as calcium antagonists and nitrates1. Although, CAS can be divided into different subtypes with different pathophysiological mechanisms that may require tailored drug treatment6. CAS can occur on an epicardial level, either focally or diffusely, throughout the epicardial coronary arteries or on a microvascular level. The former is defined as vasospastic angina (VSA) and the latter as microvascular angina (MVA) due to microvascular spasm according to the COronary VAsomotor DISorders study group (COVADIS)3,4. Moreover, combinations of endotypes of CAS may co-exist that can further complicate tailored treatment. This is especially important as the occurrence of microvascular spasm may be masked during spasm provocation when a simultaneous epicardial spasm occurs.
As a consequence, treatment of these patients in clinical practice can be cumbersome and initiates a period of trial and error based treatment with various anti-vasospastic or anti-anginal medications. Nitrates, in particular, are often initiated as first-line treatment in short-acting form as rescue medication for acute anginal attacks or in the long-acting form as maintenance therapy. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. Especially in the case of microvascular or diffuse distal epicardial spasm, the effect of NTG is controversial7,8.&#160;Furthermore, the therapeutic efficacy of chronic NTG treatment has to be weighed against potential side effects, such as severe headaches and a worsened exercise capacity9,10,11.
Recently Seitz et al. demonstrated the clinical usefulness of the ACh rechallenge technique after NTG administration as an add-on procedure to the spasm provocation test12. This is performed after a positive spasm provocation test by readministering the vasospastic dose of ACh in a similar fashion as the vasospastic dose itself 3 min after NTG administration. To this end, the COVADIS criteria are revisited in order to evaluate the preventive effect of NTG, e.g., improvement in symptoms, ischemic ECG changes, and reassessment of the site and mode of spasm by angiography3,4. Moreover, prevention of epicardial spasm&#160;during rechallenge can unmask the co-existence of microvascular spasm.
The purpose of the rechallenge after NTG, therefore, is two-fold: (1) to assess the preventive effect of NTG on the re-occurrence of spasm on a per patients level in order to improve clinical outcomes and tailor treatment immediately after diagnosis that is made during spasm provocation and (2) to assess the co-existence of microvascular spasm in patients with epicardial coronary artery spasm10,13.
A previous publication by Ong et al. extensively covered the spasm provocation test14. In our institute, we use a variation of this protocol where the ACh dosages are administered in 60 s instead of 20 s. The purpose of this paper is to describe the NTG rechallenge as an add-on procedure to the ACh spasm provocation test. This technique can be performed with each type of protocol, as demonstrated by Seitz et al. since the results of the NTG rechallenge did not differ among the participating centers that used different protocols.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Cannula (various manufacturers)</td>
			<td>BBraun</td>
			<td>4206096</td>
			<td></td>
		</tr>
		<tr>
			<td>ComboMap system</td>
			<td>Volcano-Philips</td>
			<td>Model No. 6800 (Powers Up)</td>
			<td></td>
		</tr>
		<tr>
			<td>ComboWire XT Guide Wire</td>
			<td>Volcano-Philips</td>
			<td>9515</td>
			<td>Doppler guidewire</td>
		</tr>
		<tr>
			<td>Diagnostic catheter</td>
			<td>Boston scientific</td>
			<td>34356-661</td>
			<td>H749343566610/ MODEL-6F MACH 1 JL3.5</td>
		</tr>
		<tr>
			<td>Diagnostic catheter</td>
			<td>Boston scientific</td>
			<td>34356-686</td>
			<td>H749343566860/MODEL - 6F MACH 1 JR4</td>
		</tr>
		<tr>
			<td>FINECROSS MG Coronary Micro-Guide Catheter</td>
			<td>Terumo</td>
			<td>NC-F863A</td>
			<td></td>
		</tr>
		<tr>
			<td>Intracoronary NTG</td>
			<td>hameln pharma gmbh</td>
			<td>RVG 119982</td>
			<td></td>
		</tr>
		<tr>
			<td>Lidocaine HCL</td>
			<td>Fresenius Kabi</td>
			<td>RVG 51673</td>
			<td></td>
		</tr>
		<tr>
			<td>Miochol-E Acetylcholine chloride</td>
			<td>Bausch &#38; Lomb</td>
			<td>NDC 240208-539-20</td>
			<td></td>
		</tr>
		<tr>
			<td>Sheath Radialis</td>
			<td>Teleflex</td>
			<td>AA15611S</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe- 10 mL</td>
			<td>BBraun</td>
			<td>4606108V</td>
			<td></td>
		</tr>
		<tr>
			<td>Visipaque</td>
			<td>GE Healthcare</td>
			<td>RVG 17665</td>
			<td>Iodixanol injectable contrast medium</td>
		</tr>
	</tbody>
</table>

acetylcholine re-challenge after intracoronary nitroglycerine administration

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) using acetylcholine (ACh) spasm provocation testing. CAS can further be divided into different subtypes (e.g., focal, diffuse epicardial, or microvascular spasm), each with different pathophysiological mechanisms that may require tailored drug treatment. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. In order to assess on a per-patient level whether nitroglycerine (NTG) can prevent inducible spasm, the vasospastic ACh dose can be readministered after NTG administration as part of the spasm provocation test. The preventive effect of NTG is assessed by evaluating improvements in the severity of induced symptoms, ischemic ECG changes, and by reassessing the site and mode of spasm on angiography. This technique can therefore be used to assess the nitrate responsiveness on a per-patient level and unmask co-existing microvascular spasm in patients with epicardial spasm that is prevented with NTG. The NTG rechallenge, therefore, allows to further guide targeted therapy for CAS and provide new insights into the pathophysiological mechanism behind vasospastic disorders.

Interpretation of the ACh-test and rechallenge are based on criteria defined by the COVADIS study group4. A positive diagnosis for CAS is defined as (i) reproduction of the previously reported symptoms such as chest pain, shortness of breath, or other symptoms and (ii) the induction of ischemic ECG changes (ST-segment elevation or depression, or U-waves) in reaction to ACh. (Figure 2). It is therefore important to register a 12-lead-ECG continuously throughout the tes...

Watch this Scientific Journal Video about Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration at JoVE.com

Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration

This protocol presents the acetylcholine rechallenge after nitroglycerine as an add-on procedure to spasm provocation testing. The purpose of this technique is to unmask co-existing microvascular spasm&#160;in patients with epicardial spasm&#160;and to assess the protective efficacy of nitroglycerine on a per-patient level to guide medical therapy.

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) ...

The invasive coronary function test is crucial for the diagnosis and treatment of coronary vasomotor disorders. It helps in assessing endothelial coronary dysfunction, epicardial vasospasm, and microvascular angina. The latter comprises of a vasoconstriction of abnormal dilatation of the microcirculation.This technique enables safe assessment of intracoronary administration of acetylcholine that may distinguish different endotypes of coronary vasospasm. And finally, with the use of the re-challenge method, we can identify patients with both microvascular angina and epicardial vasospasm. Begin by mixing 20 milligrams of acetylcholine with two milliliters of the solvent provided with the package.Add one milliliter of the acetylcholine solution to 499 milliliters of 0.9%sodium chloride to create the stock solution corresponding to a dosage of 20 micrograms per milliliter. Fill a sterile dish with 50 milliliters of the stock solution. Under sterile conditions, prepare five 10 milliliter syringes using the stock solution for the intracoronary injection as described in the text manuscript.For the left coronary artery, position the tip of the diagnostic catheter in the left main coronary artery. Confirm the position of the catheter by injecting two milliliters of the contrast agent. Inject five to ten milliliters of the contrast agent to visualize the coronary arteries in different projection views.Connect the Doppler guide wire to the system, and zero the pressure on the console and the aortic pressure on the hemodynamic system. Advance the Doppler guide wire through the guiding catheter into the ostium of the coronary artery with the Doppler guide wire's pressure sensor placed just distally to the tip of the guiding catheter. After normalization, reintroduce the wire via the microcatheter into the proximal or mid LAD, and acquire a stable flow signal.Document the position of the wire using fluoroscopy, and exclude any relevant epicardial stenosis. Administer the first syringe containing two micrograms of acetylcholine into the left coronary artery through the guiding wire. Inject this in 60 seconds while continuously monitoring the ECG, APV, and the patient's symptoms.After flushing the remaining acetylcholine in the guiding wire, inject 10 milliliters of contrast reagent into the catheter. Bookmark and print a 12-lead ECG after every dose of acetylcholine, or when the patient's symptoms or ECG changes occur. If diagnostic criteria are not met, administer the second syringe containing 20 micrograms of acetylcholine as demonstrated.Pause for three minutes between every dose. Inject 10 milliliters of contrasting reagent as demonstrated. If diagnostic criteria are not met after the second dose, administer the third syringe containing 100 micrograms of acetylcholine.Monitor the patient's symptoms along with ECG and APV. Then inject 10 milliliters of contrasting reagent. Inject 200 micrograms of intracoronary NTG into LAD after the test, or when severe symptoms, ischemic ECG changes, or epicardial spasms occur.Inject 10 milliliters of the syringe containing the acetylcholine dose that previously induced vasospasm into the guiding in 60 seconds while continuously monitoring the ECG, APV, and the patient's symptoms. Image the target vessel in the same projection as done in the baseline angiography after the 10 milliliters acetylcholine dose. Inject 200 micrograms of intracoronary NTG into each target vessel after the test or when severe symptoms, ischemic ECG shifts, or epicardial spasm occurs.Perform coronary angiography of the target vessel after one minute, or when the APV has returned to baseline and no symptoms are present to document reversion of spasm. The distinction between epicardial and microvascular spasms was made by comparing coronary diameter reduction in reaction to the spasm provocating dose and NTG. The coronary angiography performed during rest showed no significant lumen reduction in the LAD.At the fourth dose of acetylcholine, epicardial lumen reduction occurred together with ECG changes and recognizable symptoms, and therefore met the diagnostic criteria for epicardial vasospasm. When the coronary artery was re-challenged after intracoronary administration of NTG, some vasoconstriction occurred, although no more than 90%lumen reduction was observed, and the severity of anginal complaints was reduced. At the fourth dose, epicardial vasoconstriction causes very high APV values, whereas the preventive effect of NTG causes lower APV values because the epicardial coronary artery does not constrict.Obtaining a visual analog scale score while performing an acetylcholine re-challenge can prove helpful in quantifying the improvement in symptoms. Improvement in APV and provoked ischemic ECG changes, and the severity of vasoconstriction on angiography can help as an objective measure on the preventive effect of NTG. Continuous assessment of Doppler flow provided valuable information during spasm provocation.It provided a safety feature as flow alterations often occurred before ECG changes. With the use of this technique, we can identify patients with angina pectoris due to vasomotor disorders, and reveal the underlying mechanisms such as coronary endothelial dysfunction, coronary artery spasm, and microvascular angina.

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