We thank all the staff of the catheterization laboratory of the Tohoku University Hospital.

The measurement of myocardial lactate production during ACh provocation testing to evaluate coronary vasoreactivity was conducted following the ethical principles in the Declaration of Helsinki, and the protocol was approved by the Ethics Committees of Tohoku University (No.2016-1-643). All the patients provided written informed consent before the procedure. In this article, ACh provocation testing was performed following the guidelines of the Japanese Circulation Society9.
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<ol>
	<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=Diagnosis+of+coronary+microvascular+dysfunction+in+the+clinic.">Diagnosis of coronary microvascular dysfunction in the clinic.</a> Cardiovascular Research. 116 (4), 841-855 (2020).</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>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>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>Matsuyama, 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=Increased+plasma+level+of+endothelin-1-like+immunoreactivity+during+coronary+spasm+in+patients+with+coronary+spastic+angina.">Increased plasma level of endothelin-1-like immunoreactivity during coronary spasm in patients with coronary spastic angina.</a> American Journal of Cardiology. 68 (10), 991-995 (1991).</li><li>Goldberg, S., 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+hemodynamic+and+myocardial+metabolic+alterations+accompanying+coronary+spasm.">Coronary hemodynamic and myocardial metabolic alterations accompanying coronary spasm.</a> American Journal of Cardiology. 43 (3), 481-487 (1979).</li><li>Odaka, Y., 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=Plasma+concentration+of+serotonin+is+a+novel+biomarker+for+coronary+microvascular+dysfunction+in+patients+with+suspected+angina+and+unobstructive+coronary+arteries.">Plasma concentration of serotonin is a novel biomarker for coronary microvascular dysfunction in patients with suspected angina and unobstructive coronary arteries.</a> European Heart Journal. 38 (7), 489-496 (2017).</li><li>J. C. S. 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. 78 (11), 2779-2801 (2014).</li><li>Kaikita, 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=Determinants+of+myocardial+lactate+production+during+acetylcholine+provocation+test+in+patients+with+coronary+spasm.">Determinants of myocardial lactate production during acetylcholine provocation test in patients with coronary spasm.</a> Journal of American Heart Association. 4 (12), (2015).</li><li>Sueda, S., Kohno, H., Ochi, T., Uraoka, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Overview+of+the+acetylcholine+spasm+provocation+test.">Overview of the acetylcholine spasm provocation test.</a> Clinical Cardiology. 38 (7), 430-438 (2015).</li></ol>

H.S. received lecture fees from Bayer Yakuhin, Ltd. and Daiichi Sankyo Co. Ltd., but declares no conflicts of interest regarding the present work. All the other authors have nothing to disclose.

Detection of enhanced coronary vasoconstriction is possible by an additional pharmacological provocation testing with ACh or ergometrine during coronary angiography. Even now, there is no technique to directly visualize the coronary microvasculature for evaluation of its function in vivo, the occurrence of coronary spasm at microvascular level could be solely deduced by the reproduction of usual symptoms together with ischemic ECG changes despite the absence of epicardial coronary spasm during ACh provocation te...

Recent studies demonstrated that ischemia with non-obstructive coronary arteries (INOCA) is caused mainly by functional coronary vasomotion disorders, including epicardial and microvascular spasms1. The diagnosis of coronary vasoconstrictor dysfunction at the epicardial and/or microvascular levels often requires intracoronary provocation testing with a pharmacological vasoactive agent such as acetylcholine (ACh) during coronary angiography2. Many patients with INOCA have no epicardial spasm on coronary arteriography despite the development of angina attack and ischemic electrocardiographic (ECG) changes in response to intracoronary ACh3. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Additionally, MVS also seems to be involved in angina in a quarter of patients with vasospastic angina (VSA) due to epicardial coronary spasm4.
Since no technique is available for visualizing coronary microvessels in humans in vivo, MVS is defined as ischemic ECG changes associated with the reproduction of usual chest pain in the absence of epicardial spasm (90%) intracoronary provocation testing5. Usually, upon the development of ischemia, myocardial lactate consumption decreases, and a shift to lactate production occurs as myocardial ischemia increases in severity6,7. Thus, an additional myocardial lactate production measurement is considered to be useful in confirming ACh-induced microvascular myocardial ischemia during provocation testing3,4,8. Here, the current protocol presents coronary sinus (CS) lactate measurements for the diagnosis of MVS.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>ABL8000 FLEX blood gas analyzer</td>
			<td>RADIOMETER, Copenhagen, Denmark</td>
			<td>k041874</td>
			<td>The automatic lactate analyzer</td>
		</tr>
		<tr>
			<td>OUTLOOK</td>
			<td>Terumo Corp, Tokyo, Japan</td>
			<td>RQ-5JL4000</td>
			<td>The Judkins-left catheter for coronary angiography</td>
		</tr>
		<tr>
			<td>Ovisot for injection</td>
			<td>Daiichi sankyo company, limited, Tokyo, Japan</td>
			<td>871232</td>
			<td>Injectable product of acetylcholine chloride for acetylcholine provocation testing</td>
		</tr>
		<tr>
			<td>Supersheath</td>
			<td>MEDIKIT CO., LTD., Tokyou, Japan</td>
			<td>CS50P11TSM</td>
			<td>The sheath for insertion of a catheter</td>
		</tr>
		<tr>
			<td>Technowood SoftNAV Catheter</td>
			<td>Technowood Corp, Tokyo, Japan</td>
			<td>H710-FL445SH</td>
			<td>The Amplatz-left catheter for blood sampling from coronary sinus</td>
		</tr>
	</tbody>
</table>

measurement of myocardial lactate production for diagnosis of coronary microvascular spasm

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina attack. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Myocardial lactate production, which could be defined as a negative myocardial lactate extraction ratio (ratio of the coronary arterial-venous difference in lactate concentration to arterial concentration), is considered indicative of objective evidence to support the emerging myocardial ischemia. Thus, monitoring of the myocardial lactate production and the emergence of chest pain and ischemic electrocardiographic changes during acetylcholine (ACh) provocation testing is of significant value for detecting the entity of MVS. Practically, 1 min after incremental doses of ACh (20, 50, and 100 &#956;g) are administered into the left coronary artery (LCA), paired samples of 1 mL of blood are collected from the LCA ostium and coronary sinus for measurement of lactate concentration by a calibrated automatic lactate analyzer. Then, the development of MVS could be confirmed by negative myocardial lactate extraction ratio despite the absence of angiographically demonstrable epicardial coronary spasm or before its occurrence throughout ACh provocation testing. In conclusion, assessment of myocardial lactate production is essential and valuable for the diagnosis of MVS.

A 56-year-old woman with no coronary risk factors suffered from transient chest discomfort at rest. She underwent ACh provocation testing and measurement of myocardial lactate production for diagnosis of MVS. As shown in Figure 2, chest pain, ischemic ECG changes, and negative LER were noted immediately following 100 &#181;g of ACh administration into the LCA. Still, no relevant epicardial coronary spasm was observed on angiography. Thus, she was diagnosed as having MVS. Intriguingly, she ha...

Watch this Scientific Journal Video about Measurement of Myocardial Lactate Production for Diagnosis of Coronary Microvascular Spasm at JoVE.com

Measurement of Myocardial Lactate Production for Diagnosis of Coronary Microvascular Spasm

Myocardial lactate production (coronary arterial-venous difference in serum lactate level) during coronary spasm provocation testing is considered as a highly sensitive marker that reflects acetylcholine-induced myocardial ischemia due to microvascular spasm. This article presents the procedures to assess myocardial lactate production for the diagnosis of coronary microvascular spasm.

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina ...

Assessment of myocardial lactate production during Ach-provocation testing is essential and viable for diagnosing coronary microvascular spasms. This procedure is generally safe and straightforward for detecting the occurrence of a microvascular spasms, which is typically not visible on any other imaging device Before starting the procedure, ensure that myocardial lactate production is measured in patients undergoing acetylcholine provocation testing to diagnose vasospastic angina or microvascular angina due to vasospasm. Additionally, ensure that the patients have discontinued all vasoactive agents at least 48 hours before the catheterization.Next, shave the patient's hair at puncture sites including both inguinal regions and wrists. After anesthetizing, the puncture sites place two five French venous sheaths through the right or left femoral vein with ultrasound guidance. Then place a five or six French arterial sheath through the radial or femoral artery.Next, administer intravenous heparin to achieve therapeutic anticoagulation before coronary instrumentation. Cannulate a five or six French Judkins left catheter into the left coronary artery or LCA through the radial or femoral artery. Next advance a coronary sinus or CS catheter from a venous sheath placed at the right femoral vein to the right atrium.Then confirm the configuration of the CS and the location of its orifice in the right atrium in advance by detecting the CS image in the venous phase of LCA angiography. Next, cannulate an Amplatz left catheter into the CS by turning the catheter counterclockwise at the right atrium with the left anterior oblique view. Then verify whether the catheter is cannulated into the CS and its position in the CS is adequate by contrast injection from the catheter end.Next, take a pair of blood samples from the CS and the osteum of LCA simultaneously to examine myocardial lactate metabolism at baseline. Finally, measure the lactate levels in the samples using blood gas analysis equipped with an automatic lactate measurement function. Perform the baseline left coronary angiography in an appropriate projection that ensures the best separation of the branches of each coronary artery.Next, administer acetylcholine into the coronary artery in a cumulative manner over 20 seconds with careful monitoring of blood pressure and 12 lead ECG. Perform a coronary angiography when chest pain or any ECGST segment change occurs or routinely after completing each acetylcholine injection, collect paired samples of one milliliter blood from the LCA osteum and the CS to measure lactate concentrations at one minute after each dose of acetylcholine is given to the LCA and determine lactate concentrations with a calibrated automatic lactate analyzer. Calculate the lactate extraction ratio or LER by dividing the coronary arteriovenous difference in the lactate concentration by the arterial lactate concentration.If epicardial coronary spasms are induced, administer five milligrams of isosorbide dinitrate into the LCA and promptly perform coronary angiography while the coronary artery is maximally dilated. Simultaneously collect one milliliter of blood from the LCA osteum and the CS to measure lactate concentrations after relieving the acetylcholine induced spasm. Shown here are the coronary angiograms, ECG changes, and lactate levels during acetylcholine provocation testing of a 56-year-old female patient suffering from transient chest discomfort at rest.Baseline coronary angiogram of LCA and ECG findings appeared normal. Chest pain ischemic ECG changes and negative LER were noted immediately after 100 micrograms of acetylcholine administration into the LCA. Still no relevant epicardial coronary spasm was observed on angiography.Thus, she was diagnosed as having a microvascular spasm. Interestingly, persistent negative LER was observed even after isosorbide dinitrate was administered into the LCA suggesting that myocardial ischemia attributable to impaired bioavailability of nitric oxide in coronary pre arterials was prolonged. The location of CS orifice must be confirmed in advance by detecting the CS image in the venous face of LCA angiography.

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1.3K Görüntüleme.  Tohoku University Graduate School of Medicine. Ach-provokasyon testi sırasında miyokardiyal laktat üretiminin değerlendirilmesi, koroner mikrovasküler spazmların teşhisi için gerekli ve uygundur. Bu prosedür, tipik olarak başka herhangi bir görüntüleme cihazında görünmeyen bir mikrovasküler spazmların oluşumunu tespit etmek için genellikle güvenli ve basittir Prosedüre başlamadan önce, vazospazm nedeniyle vazopastik anjina veya mikrovasküler anjina tanısı koymak için asetilkolin provokasyon testi yapılan hasta...