Name: intracoronary acetylcholine provocation testing for assessment of coronary vasomotor disorders
Uploaded: 2016-08-18T14:00:00
Description: Watch this Scientific Journal Video about Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders at JoVE.com

This project is supported in part by grant KKF-15-1.

NOTE: Intracoronary acetylcholine testing has been approved by the local ethics committee and the protocol follows the guidelines of our institution for human research.
1. Preparation of the Acetylcholine Solutions (See Materials Table)
<ol>
	<li>Mix the 20 mg acetylcholine with the 2 ml solvent provided with the package.</li>
	<li>Add the 2 ml ACH solution to 98 ml of NaCl 0.9 %. This corresponds to a dose of 0.2 mg/ml and is called stock solution 1. Add 9 ml of stock solution 1 to 91 ml of...

<ol>
	<li>Prinzmetal, M., Kennamer, R., Merliss, R., Wada, T., Bor, N. <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.+I.+A+variant+form+of+angina+pectoris;+preliminary+report.">Angina pectoris. I. A variant form of angina pectoris; preliminary report.</a> Am J Med. 27, 375-388 (1959).</li><li>Cheng, T. O., Bashour, T., Kelser, G. A., Weiss, L., Bacos, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Variant+angina+of+Prinzmetal+with+normal+coronary+arteriograms.+A+variant+of+the+variant.">Variant angina of Prinzmetal with normal coronary arteriograms. A variant of the variant.</a> Circulation. 47 (3), 476-485 (1973).</li><li>Yasue, 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=Induction+of+coronary+artery+spasm+by+acetylcholine+in+patients+with+variant+angina:+possible+role+of+the+parasympathetic+nervous+system+in+the+pathogenesis+of+coronary+artery+spasm.">Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm.</a> Circulation. 74 (5), 955-963 (1986).</li><li>Bell, M. R., Berger, P. B., Holmes, D. R., Mullany, C. J., Bailey, K. R., Gersh, B. 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R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quality+of+life,+employment+status,+and+anginal+symptoms+after+coronary+angioplasty+or+bypass+surgery.+3-year+follow-up+in+the+Randomized+Intervention+Treatment+of+Angina.">Quality of life, employment status, and anginal symptoms after coronary angioplasty or bypass surgery. 3-year follow-up in the Randomized Intervention Treatment of Angina.</a> Circulation. 94 (2), 135-142 (1996).</li><li>Ong, P., Athanasiadis, A., Borgulya, G., Mahrholdt, H., Kaski, J. C., 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=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> J Am Coll Cardiol. 59 (7), 655-662 (2012).</li><li>Furchgott, R. F., Zawadzki, J. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+obligatory+role+of+endothelial+cells+in+the+relaxation+of+arterial+smooth+muscle+by+acetylcholine.">The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.</a> Nature. 288 (5789), 373-376 (1980).</li><li>Shimizu, H., Lee, J. D., Ogawa, K., Hara, A., Nakamura, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coronary+artery+vasoreactivity+to+intracoronary+acetylcholine+infusion+test+in+patients+with+chest+pain+syndrome.">Coronary artery vasoreactivity to intracoronary acetylcholine infusion test in patients with chest pain syndrome.</a> Intern Med. 31 (1), 22-27 (1992).</li><li>Montalescot, G., 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=2013+ESC+guidelines+on+the+management+of+stable+coronary+artery+disease:+the+Task+Force+on+the+management+of+stable+coronary+artery+disease+of+the+European+Society+of+Cardiology.">2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology.</a> Eur Heart J. 34 (38), 2949-3003 (2013).</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> Circ J. 78 (11), 2779-2801 (2014).</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=Patterns+of+coronary+vasomotor+responses+to+intracoronary+acetylcholine+provocation.">Patterns of coronary vasomotor responses to intracoronary acetylcholine provocation.</a> Heart. 99 (17), 1288-1295 (2013).</li><li>Seldinger, S. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catheter+replacement+of+the+needle+in+percutaneous+arteriography;+a+new+technique.">Catheter replacement of the needle in percutaneous arteriography; a new technique.</a> Acta radiol. 39 (5), 368-376 (1953).</li><li>Judkins, M. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+coronary+arteriography.+I.+A+percutaneous+transfemoral+technic.">Selective coronary arteriography. I. A percutaneous transfemoral technic.</a> Radiology. 89 (5), 815-824 (1967).</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> Lancet. 351 (9110), 1165-1169 (1998).</li><li>Chandrasekar, B., 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=Complications+of+cardiac+catheterization+in+the+current+era:+a+single-center+experience.">Complications of cardiac catheterization in the current era: a single-center experience.</a> Catheter Cardiovasc Interv. 52, 289-295 (2001).</li><li>Nakao, K., 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=Hyperventilation+as+a+specific+test+for+diagnosis+of+coronary+artery+spasm.">Hyperventilation as a specific test for diagnosis of coronary artery spasm.</a> Am J Cardiol. 80 (5), 545-549 (1997).</li></ol>

It is feasible to implement the acetylcholine test in daily clinical routine in the catheterisation laboratory. Apart from the preparation of the ACH solutions there are several technical issues that have to be resolved before starting the test including radiolucent ECG leads for continuous 12-lead ECG registration. This is essential to be able to detect transient ischemic ECG changes during the test. Moreover, it is important to know that the ACH solutions can only be used for 2 hr. After that they should be newly prepa...

Angina pectoris is the hallmark of coronary artery disease and the concept of an epicardial stenosis causing myocardial ischemia and exercise-induced angina has been established for many years. However, many patients with angina pectoris do not have the typical triad of retrosternal pain, onset during exercise and relief by nitroglycerine or rest. Frequently patients report angina pectoris at rest or a combination of exertional and resting angina as well as shortness of breath upon exertion as a possible angina equivalent. In 1959 Prinzmetal was the first to introduce the concept of transient spasm of the coronary arteries causing angina at rest associated with ST-segment elevation on the electrocardiogram (ECG) but with preserved exercise capacity1. This hypothesis was confirmed later using coronary angiography and it appeared that coronary spasm can be present in patients with epicardial stenoses or normal coronary arteries2. In the 1980ies intracoronary acetylcholine provocation testing (ACH-test) for the detection of coronary artery spasm was established in Japan and subsequently the interested in clinical research for coronary spasm increased3.
However, after introduction of percutaneous coronary intervention in 1977 and the first stent implantation in 1986 the interest in coronary vasomotor disorders declined considerably at least in Europe and the United States. This may be also due to the invasive nature of the ACH-test (due to the short half-life of ACH it can only be administered into the coronary arteries for the assessment of coronary spasm). Still, many patients with signs and symptoms of myocardial ischemia do not have any relevant epicardial stenosis on coronary angiography4,5,6. In such patients intracoronary acetylcholine provocation testing is useful to detect a clinically relevant coronary vasomotor disorder and institute appropriate medical therapy7.
Acetylcholine is a neurotransmitter in the parasympathetic nervous system. It acts via nicotinergic as well as muscarinergic (mAChR) receptors. The latter are important for vascular homeostasis and acetylcholine binds on mAChR as a non-selective agonist. Activation of these receptors at the endothelial level leads to nitric oxide mediated vasodilatation whereas activation of mAChR on the vascular smooth muscle cells leads to vasoconstriction8. Depending on the integrity of the endothelium and the reactivity of the smooth muscle cells the net effect of intracoronary acetylcholine administration is vasodilatation or vasoconstriction. The physiologic response of coronary arteries in response to acetylcholine in human beings is not fully understood but it has been reported that vasodilatation as well as vasoconstriction of up to 25% of the vessel diameter may be physiologic as shown in patients with normal coronary arteries and no angina pectoris9.
Intracoronary acetylcholine provocation testing has been recommended by the European Society of Cardiology guidelines10 as well as the Japanese Circulation Society guidelines11 for assessment of epicardial and/or microvascular spasm in patients with angina pectoris and unobstructed coronary arteries. Intracoronary acetylcholine provocation testing has been established in daily clinical routine in the catheterization laboratory of our institution in 2003. Since 2006 a standardized protocol has been followed12. ACH-testing is generally performed in all patients with signs and symptoms of myocardial ischemia yet no relevant epicardial stenosis (&#60;50%) on coronary angiography. ACH-testing is performed immediately after diagnostic coronary angiography according to the protocol described below. Ergonovine is another agent that is used for spasm provocation testing with a different mechanism of action. Detailed information on ergonovine testing can be found elsewhere12.

<table border="0" cellpadding="0" cellspacing="0" width="923">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:528px;">Vial of 20 mg acetylcholine chloride powder and 1 Ampoule of 2 mL diluent</td>
			<td style="width:151px;">Bausch &#38; Lomb&#160;</td>
			<td style="width:165px;">NDC 24 208-539-20</td>
			<td style="width:80px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">3 x 100 ml NaCl 0.9 %</td>
			<td>BBraun</td>
			<td>3200950</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">3 x syringe 50 ml each</td>
			<td>BBraun</td>
			<td>4187903</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">&#160;1 x 2 ml syringe</td>
			<td>BBraun</td>
			<td>4606027V</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">&#160;1 x 10 ml syringe</td>
			<td>BBraun</td>
			<td>4606108V</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">2 x cannula 20 G 70mm</td>
			<td>BBraun</td>
			<td>4665791</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">&#160;5 x 5 ml syringe</td>
			<td>BBraun</td>
			<td>4606051V</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Contrast agent Imeron 350 with a 10ml syringe for contrast injection</td>
			<td>Bracco Imaging</td>
			<td>30699.03.00</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Coronary angiography suite (AXIOM Artis MP eco )</td>
			<td>Siemens</td>
			<td>n/a</td>
			<td></td>
		</tr>
	</tbody>
</table>

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.

Interpretation of the acetylcholine test is based on three criteria. First, the patient is asked throughout the test whether or not symptoms occur. Frequently, patients report a reproduction of their usual symptoms such as chest pain, shortness of breath or other symptoms. This represents an important point for the overall interpretation of the test. Second, a 12-lead-ECG registration is continuously performed throughout the test with a special emphasis on ischemic ECG shifts such as ST-s...

Watch this Scientific Journal Video about Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders at JoVE.com

Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders

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 ...

The overall goal of the Acetylcholine Test is to assess whether a patient suffers from a coronary vasomotor disorder such as an epicardial or coronary microvascular spasm. The acetylcholine test is helpful for detecting a coronary vasomotor disorder. Especially in patients with angina pectoris and unobstructed coronary arteries.The wonderful thing about the acetylcholine test is that you can perform it immediately after diagnostic angiography. And it doesn't cost a lot of money and it doesn't take a lot of time. Before beginning the procedure, mix 20 milligrams of acetylcholine with two milliliters of the acetylcholine solvent.Then mix two milliliters of the resulting acetylcholine solution with 98 milliliters of 0.9%sodium chloride. Next add nine milliliters of this 0.2 milligram per milliliter acetylcholine solution with 91 milliliters of sodium chloride to achieve an 18 microgram per milliliter aceteylcholine solution and label the container High"Fill a 50 milliliter profusion syringe with 40 milliliters of the 18 microgram per milliliter acetylcholine solution. Then transfer eight milliliters of the acetylcholine solution from the High"syringe into a second 50 milliliter profusion syringe and add 32 milliliters of sodium chloride into the second syringe to achieve a 3.6 microgram per milliliter acetylcholine dose.Label this syringe Medium"Transfer four milliliters of the medium concentration of acetylcholine into a third 50 milliliter profusion syringe. Add 36 milliliters of sodium chloride to the third syringe to obtain a 0.36 microgram per milliliter acetylcholine dose. And label this syringe Low"After injecting local anesthesia in proximity to the patient's right radial artery, confirm that the region is numb.Then place a catheter according to standard protocols. After visually excluding any epicardial stenosis, inject six liters of the two microgram Low"acetylcholine dose into the left coronary artery over the course of 20 seconds while monitoring ECG and the patient's symptoms. Then inject 10 milliliters of contrast agent manually via a contrast syringe into the catheter to visualize the coronary arteries.After one minute inject six milliliters of the 20 microgram Medium"acetylcholine dose into the left coronary artery as performed for the low dose. Follow this by injecting 10 milliliters of contrast agent. After another minute, repeat the injection with 5.5 milliliters of the 100 microgram High"acetylcholine dose.Again follow the acetylcholine injection with 10 milliliters of contrast agent. Most patients will develop symptoms, ECG changes, or an epicardial spasm at this dose. If bradycardia is observed on the ECG, reduce the speed of the injection and observe the ECG carefully.If no spasm has occurred after one minute, administer 11 milliliters of the 200 microgram High"acetylcholine dose. Followed by 10 milliliters of contrast agent. If no abnormal findings are observed, inject 4.5 milliliters of the 80 microgram acetylcholine dose into the right coronary artery as just demonstrated followed by 10 milliliters of contrast agent.Then inject 200 microgram of intracoronary nitroglycerin into each tested artery and image the vessel after one minute as just demonstrated to document the reversion of the spasm. Epicardial coronary spasm is diagnosed when an epicardial vasoconstriction greater than or equal to 90%compared to the relaxed state after nitroglycerin administration together with ischemic ECG shifts and a reproduction of the patient's symptoms are observed. A microvascular spasm is diagnosed in the case of a reproduction of the patient's symptoms with ischemic ECG shifts, usually ST segment depression during the acetylcholine test without any epicardial vasoconstriction greater than or equal to 90%Remember that the interpretation of the acetylcholine test is based on patient's symptoms, ECG shifts, and the angiographic appearance of the coronary arteries during the test.I hope this video will encourage interventional cardiologists to incorporate the acetylcholine test into their diagnostic armamentarium because the result of this test informs about the patient's symptoms, the cause of the patient's symptoms and it helps to select the appropriate treatment.

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