Overview of the pharmacological spasm provocation test: Comparisons between acetylcholine and ergonovine

Journal of Cardiology 69 (2017) 57–65

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Review

Overview of the pharmacological spasm provocation test: Comparisons between acetylcholine and ergonovine Shozo Sueda (MD, FJCC)a,*, Hiroaki Kohno (MD)b, Takaaki Ochi (MD)c, Tadao Uraoka (MD)d, Kensuke Tsunemitsu (MD)e a

Department of Cardiology, Ehime Prefectural Niihama Hospital, Ehime, Japan Department of Cardiology, Tsukazaki Hospital, Himeji, Hyogo, Japan Department of Cardiology, Ochi Clinic, Iyogun Masaki Chou, Ehime, Japan d Department of Cardiology, Uraoka Clinic, Ozu, Ehime, Japan e Department of Surgery, Saiseikai Saijo Hospital, Saijo, Ehime, Japan b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 10 July 2016 Received in revised form 15 September 2016 Accepted 23 September 2016 Available online 15 November 2016

The spasm provocation tests of ergonovine and acetylcholine have been employed in the cardiac catheterization laboratory. Ergonovine acts through the serotogenic receptors, while acetylcholine acts through the muscarinic cholinergic receptors. Different mediators may have the potential to cause different coronary responses. However, there are few reports concerning the coronary response between ergonovine and acetylcholine in the same patients. Acetylcholine is supersensitive for females; spasm provoked by ergonovine is focal and proximal, whereas provoked spasm by acetylcholine is diffuse and distal. We should use both tests as supplementary in the clinic because ergonovine and acetylcholine have self-limitations to induce coronary spasms during daily life. The maximal pharmacological doses, administration methods, and the angiographical positive definition are remarkably different for each institution in the world. We recommend the pharmacological spasm provocation tests as Class I in the guidelines in patients with vasospastic angina throughout the world. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Keywords: Acetylcholine Ergonovine Spasm Vasospastic angina

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . In our experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History of ER and ACh tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spasm provocation test of ER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Procedures of ER spasm provocation test . . . . . . . . . . . . . . . . . . Positive spasm definition and spasm configuration . . . . . . . . . . Indication and exclusion criteria for ER spasm provocation test Maximal ER dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spasm provocation test of ACh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Procedures of ACh test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Indication and exclusion criteria of ACh test. . . . . . . . . . . . . . . . Advantages and disadvantages of ACh test . . . . . . . . . . . . . . . . . Incidence of provoked spasm by ER and ACh tests . . . . . . . . . . . . . . . . Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Difference between ACh and ER tests . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: The Department of Cardiology, Ehime Niihama Prefectural Hospital, Hongou 3 choume 1-1, Niihama City, Ehime 792-0042, Japan. Fax: +81 897 41 2900. E-mail address: [email protected] (S. Sueda). http://dx.doi.org/10.1016/j.jjcc.2016.09.012 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

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Investigation of microvascular dysfunction in patients with VSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison with international group [Coronary Vasomotion Disorders International Study Group (COVADIS)] . ACh and ER tests hereafter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

History of ER and ACh tests

Coronary artery spasm may concern the pathogenesis of various cardiac disorders, such as acute coronary syndrome, unstable angina, serious fatal arrhythmia, sudden cardiac death, syncope, transient heart failure, atypical chest pain, and so on [1–7]. In the clinical situations, we finally decided to perform spasm provocation tests of acetylcholine (ACh) and ergonovine (ER) as invasive methods in patients suspected of vasospastic angina (VSA). Hackett et al. and Ishise et al. reported the usefulness of intracoronary injection of ER in diagnosing patients with VSA in 1987 [8,9]. In contrast, Yasue and Okumura reported the usefulness of intracoronary administration of ACh in patients with variant angina in 1988 [10–12]. Instead of intravenous injection of ER, cardiologists have employed intracoronary administration methods of ACh and ER. ACh acts through the muscarinic cholinergic receptors, whereas ER probably acts through the serotogenic receptors. Different mediators may have different coronary response even in the same patients. However, the majority of cardiologists use one pharmacologic agent, ACh or ER, to diagnose the presence of coronary artery spasm in the cardiac catheterization laboratory. We performed the ACh and ER spasm provocation tests for 24 years. However, there are some controversies concerning the diagnostic utility, limitations, and complications of pharmacological spasm provocation tests. According to the Japanese Circulation Society (JCS) guidelines for VSA established in 2008, selective methods of ACh and ER tests are recommended as invasive methods to diagnose patients when suspecting coronary spasm [13]. In the JCS guidelines, the pharmacological spasm provocation test is defined as Class I, whereas the European Society of Cardiology (ESC) guideline and the American College of Cardiology (ACC)/American Heart Association (AHA) guideline give the spasm provocation testing Class IIa and Class IIb, respectively [14,15]. In this article, we summarize the comparisons of clinical usefulness between ACh and ER tests in the clinic.

As shown in Table 1, Stein et al. first reported the usefulness of intravenous injection of ER in diagnosing coronary insufficiency in 1949 [16]. In 1972, the first ER spasm provocation test was employed at the Cleveland Clinic during cardiac catheterization [17]. In contrast, Yasue et al. reported that subcutaneous injection of methacholine induced an attack of variant angina or coronary artery spasm in 1974 [18]. Subsequently, Endo reported the coronary arteriogram and ventriculogram during attack induced by methacholine in Prinzmetal’s variant angina in 1976 [19]. Schroeder et al. reported the clinical result of intravenous ER testing in 57 patients in 1977 and Waters et al. also reported the ER testing in coronary care unit in 1980 [20,21]. Curry et al. reported the similarities of ER-induced and spontaneous attacks of variant angina in 1979 [22]. Yasue et al. reported that intracoronary injection of ACh induced coronary spasm and attack in patients with variant angina and that the activity of the parasympathetic nervous system may play a role in the pathogenesis of coronary spasm in 1986 [10]. Hackett et al. and Ishise et al. reported the usefulness of intracoronary administration of ER instead of intravenous injection of ER in 1987 [8,9]. Okumura and Yasue et al. reported that sensitivity of the intracoronary injection of ACh was 90% in variant angina and specificity of the intracoronary injection of ACh was 99%, and that multivessel coronary spasm was often observed in patients with variant angina by using intracoronary injection of ACh in 1988 [11,12]. Since then, spasm provocation test of ACh has become a popular test for the induction of coronary artery spasm in the cardiac catheterization laboratory in Japan instead of intravenous injection of ER. The spasm provocation test is not broadly employed outside Asia, for example neither in the USA nor in Europe. In 2008, Ong et al. reported the coronary artery spasm as a frequent cause of acute coronary syndrome by using intracoronary ACh testing [23]. Recently, Ong et al. also reported the clinical usefulness of intracoronary ACh provocation tests in 921 consecutive white patients [24]. However, there are few papers about simultaneous or continuous ACh and ER tests in the same patients, because ER is not available in many countries.

In our experience Between January 1991 and December 2014, we performed 1634 ACh spasm provocation tests and 1152 selective ER spasm provocation tests. During this period, we performed a total of 7622 coronary angiography procedures including 2002 percutaneous coronary intervention procedures and 5620 diagnostic/ follow-up cardiac catheterizations. We performed ACh spasm provocation tests in more than a quarter patients with diagnostic/follow-up catheterization (29.1%; 1634/5620) and ER tests in approximately one-fifth of those patients (20.5%; 1152/5620). We tried to perform the selective spasm provocation tests to examine the incidence of provoked spasm in patients who had undergone coronary angiography as much as possible. During the same periods, we also performed both ACh and ER tests in 496 patients, and added intracoronary injection of ACh just after ER tests in 271 patients. We had no experience of intravenous ER tests.

Spasm provocation test of ER Procedures of ER spasm provocation test The JCS guidelines recommended that cardiologists should perform the ER spasm provocation test after patients have discontinued medications for 48 h [13]. However, we have employed at least 24 h cessation of medications before performing the spasm provocation test of ER to avoid precipitating cardiac events due to coronary spasm because patients are off medications before admission. We recommend performing the ER spasm provocation test in the morning whenever possible. Provocation of coronary artery spasm is performed with an intracoronary injection of ER. Pharmacological characteristics of ER compared with ACh are shown in Table 2. ER (Ergometrine injection F,

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Table 1 History of both ER and ACh tests. Author

Year

Journal

1949 1972

Stein [16] Heupler et al. [17]

Am Heart J Am J Cardiol

1974

Yasue et al. [18]

Circulation

1976

Endo et al. [19]

N Engl J Med

1977 1979 1980 1980 1982

Schroeder et al. [20] Curry et al. [22] Waters et al. [21] Buxton et al. [46] Bertrant et al. [41]

Am J Cardiol Circulation Am J Cardiol Am J Cardiol Circulation

1986 1987

Yasue et al. [10] Nosaka et al. [42]

Circulation J Cardiol

1987 1987 1988

Hackett et al. [8] Ishise et al. [9] Okumura et al. [12]

Circulation Kokyu To Junkan Circulation

1988

Okumura et al. [11]

J Am Coll Cardiol

1992

Harding et al. [47]

J Am Coll Cardiol

1992 1997 1999 2000 2000

Suzuki et al. [50] Kanazawa et al. [51] Sueda et al. [43] Sueda et al. [49] Sueda et al. [55]

Am Heart J Clin Cardiol Am J Cardiol Am J Cardiol Jpn Circ J

2003

Sueda et al. [52]

Coron Artery Dis

2004 2004

Sueda et al. [44] Sueda et al. [45]

Angiology Coron Artery Dis

2008 2014

Ong et al. [23] Ong et al. [24]

J Am Coll Cardiol Circulation

Report issue The usefulness of intravenous injection of ER in diagnosing coronary insufficiency ER spasm provocation test was firstly employed in Cleveland clinic during cardiac catheterization in the world Subcutaneous injection of methacholine induced an attack of variant angina or coronary artery spasm Coronary arteriogram and ventriculogram during attack induced by methacholine in Prinzmetal’s variant angina Clinical result of intravenous ER tests in 57 patients Similarities of ER-induced and spontaneous attacks of variant angina ER testing in a coronary care unit Refractory ER-induced vasospasm: importance of intracoronary nitroglycerine Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography Intracoronary injection of ACh induced coronary spasm in patients with variant angina: possible role Coronary arterial spasm and symptomatology in ischemic and nonischemic heart disease: study of the ER maleate provocation test in 3000 consecutive patients Induction of coronary artery spasm by a direct local action of ER Usefulness of intracoronary administration of ER to provoke coronary artery spasm Multivessel coronary spasm often observed in patients with variant angina by using intracoronary injection of ACh Sensitivity of the intracoronary injection of ACh was 90% in variant angina and specificity of the intracoronary injection of ACh was 99% ER maleate testing during cardiac catheterization: a 10-year perspective in 3447 patients without significant coronary artery disease or Prinzmetal’s variant angina Induction of coronary artery spasm by intracoronary ACh: comparison with intracoronary ER Disparity between serotonin- and acetylcholine-provoked coronary spasm Spasm provoked frequency by ACh test in consecutive 685 Japanese patients Major complications during ACh test New combined spasm provocation test in patients with rest angina: intracoronary injection of ACh after intracoronary administration of ER Induction of coronary artery spasm by two pharmacologic agents: comparison between intracoronary injection of ACh and ER Spasm provoked frequency by ER test in consecutive 596 Japanese patients Clinical impact of selective spasm provocation tests: comparisons between ACh and ER in 1508 examinations Coronary artery spasm as a frequent cause of acute coronary syndrome: the CASPAR study Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries

ACh, acetylcholine; ER, ergonovine.

0.2 mg/ml; Fuji Seiyaku, Tokyo, Japan) in 0.9% warm saline solution was injected as 16 mg/min for 4 min for a maximal dose of 64 mg into the left coronary artery (LCA) and as 10 mg/min over 4 min for a total dose of 40 mg into the right coronary artery (RCA), with at least a 5-min interval between each injection. If systolic blood pressure was >190 mmHg before performing ER tests, we did not perform ER tests in these patients. We do not recommend single bolus injection of ER to avoid severe complications.

Coronary angiography is performed when either ST-segment changes or chest pain (or both) occurred, or after 2 min following the completion of each injection. Intracoronary injection of ER into the responsible vessel is not performed if coronary artery spasm occurred spontaneously during coronary angiography. When a coronary spasm is induced and does not resolve spontaneously within 3 min after the completion of ER injection, or when hemodynamic instability due to the coronary spasm

Table 2 Comparisons of pharmacological characteristics between ergonovine and acetylcholine. Pharmacological agent Ergometrine

Pharmacological structural formula

Circulatory action

a-Blocker

Binding receptor

Action site

Serotogenic receptor

Smooth muscle

Muscarinic cholinergic receptor

Endothelium Smooth muscle

Vasoconstriction

Acetylcholine

Vasodilatation Vasoconstriction Bradycardia

S. Sueda et al. / Journal of Cardiology 69 (2017) 57–65

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occurred, 2.5–5.0 mg of nitrate is injected into the responsible vessel. During the study, arterial blood pressure and an electrocardiogram are continuously monitored on an oscilloscope. A standard 12-lead electrocardiogram (ECG) is recorded every 30 s. We recommend performing some test shots at about 30-s intervals with a small amount of contrast medium during ER testing, if necessary. We also recommend trying to perform coronary angiography before coronary spasm when complete obstruction is induced by pharmacologic agents. Moreover, ECG changes should be checked without administration of contrast medium or ER or saline into the responsible vessel for at least 30–60 s. We should report ER test negative but not negative for coronary spasm when intracoronary injection of ER dose not provoke spasm. Positive spasm definition and spasm configuration The JCS guidelines [13] define the positive coronary artery spasm as transient luminal narrowing >90% and ischemic ECG findings. A finding of usual chest pain is not always a requirement. Patients with catheter-induced spasms should be excluded. Catheter-induced spasms are often observed in the RCA proximal and rarely in left main trunks. In these situations, after spontaneous relief without administration of nitrates, one should perform ER spasm provocation test. As configuration of provoked spasms, we often recognize diffuse transient narrowing during ER spasm provocation tests. Focal spasm is defined as a discrete transient vessel narrowing of >90% localized in the major and branch coronary artery. Diffuse spasm is diagnosed when a transient vessel narrowing is 90% compared to the baseline coronary angiography observed from the proximal to the distal segment in the 3 major coronary arteries and branches. Angiographically evident stenosis of positive spasm, the spasm site according to the AHA classification [25], the spasm configuration and real-time symptoms except for chest pain or oppression are necessary issues in ER spasm provocation test summary. Indication and exclusion criteria for ER spasm provocation test We did not perform the provocation test if patients had left main narrowing (>50%), triple-vessel disease, two-vessel disease with total occlusion, heart failure (New York Heart Association Class III or IV), renal failure (creatinine >2.0 mg/dl), spontaneous spasm was found, or nitrate was initially used to relieve spasms in the coronary artery tested. We also did not perform spasm provocation tests if the patients were to undergo multiple coronary

angioplasties or bypass surgery. However, in patients with multiple organic stenosis and rest angina, we recommended performing the ER spasm provocation test to clarify the presence of coronary spasm. We performed ER spasm provocation tests except for patients with the above exclusion criteria as much as possible when suspecting coronary artery spasm, because coronary artery spasm may be present irrespective of atypical or silent symptoms. Maximal ER dose According to the JCS guidelines, maximal ER dose is 20–60 mg in the RCA and LCA [13]. In Table 3, we showed that the intracoronary cumulative maximal ER dose was 50 mg in each coronary artery in the majority of past reports [26–33]. However, in some reports, the intracoronary cumulative ER dose on both coronary arteries was more than 50 mg [34–36]. Many cardiologists performed selective ER tests in each hospital, whereas the administration methods and maximal ER dose were remarkably different at each institution. Some cardiologists performed the incremental ER dose up or bolus injection, whereas other cardiologists performed the continuous intracoronary administration of ER. We had no standard technique of intracoronary ER spasm provocation tests. Worldwide, we should establish the gold standard of selective ER spasm provocation tests. As shown in Table 3, maximal ER dose of each coronary artery was approximately 50 mg in many past reports. We recommend 40–60 mg of intracoronary injection of ER in each coronary artery for 2–4 min to avoid serious complications due to bolus administration. Spasm provocation test of ACh Procedures of ACh test The JCS guidelines recommended that cardiologists should perform the ACh spasm provocation test after patients have discontinued medication for 48 h [13]. A bipolar electrode catheter is inserted into the right ventricular apex through the femoral or antecubital vein and is connected to a temporary pacemaker set at the rate of 40–45 beats/min. We recommend performing ACh spasm provocation test in the morning whenever possible. Provocation of coronary artery spasm is performed with an intracoronary injection of ACh. Pharmacological characteristics of ACh are shown in Table 2. ACh chloride (Neucholin-A, 30 mg/2 ml; Zeria Seiyaku, Tokyo, Japan) is injected in incremental doses of 20, 50, and 100 mg into the LCA first and of 20 and 50 mg into the RCA over 20 s with at least a 3-min interval between each injection,

Table 3 Comparisons of intracoronary ER procedures in the past. Year

Author

RCA dose of ER (mg)

LCA dose of ER (mg)

Total maximal dose (mg)

Infusion time (s)

1987 1987 1988 1989 1991 1991 1992 1993 1997 1998 2004 2006 2007 2008 2010 2011

Hackett et al. [8] Ishise et al. [9] Mohri et al. [26] Fournier et al. [27] Kaski et al. [30] Toyo-oka et al. [34] Suzuki et al. [50] Fukai et al. [35] Kanazawa [51] Yamada et al. [36] Sueda et al. [44] Coma-Canella et al. [29] Hung et al. [28] Cheng et al. [31] Kim et al. [33] Yun et al. [32]

1/5/10/30 10–40 5/10/35 25/25 20 20/40/60 1/5/10/30 5/10/50 40 25/50 40 1/5/10/30 1/5/10/30 1/5/10/30 5/10/30 40

1/5/10/30 10–40 5/10/35 25/25 20 20/40/60 1/5/10/30 5/10/50 40 25/50 64 1/5/10/30 1/5/10/30 1/5/10/30 5/10/30 64

100 80 100 100 40 240 92 130 80 150 104 92 92 92 90 104

>60 300 20–30

RCA, right coronary artery; LCA, left coronary artery; ER, ergonovine; TIMI, thrombolysis in myocardial infarction.

Interval (min) 5 3 3

3–5 >30

3

240

5

240

3 3 3 5

Positive spasm >90% Total Total or 75% >90% >90% >75% 90% Total or TIMI I >99% Total or >50% >70% >70–90% >70%

S. Sueda et al. / Journal of Cardiology 69 (2017) 57–65

according to the original method proposed by Yasue and Okumura [10–12]. In addition, we employed the maximal dose of 80 mg into the RCA and 200 mg into the LCA if the first injections do not provoke spasm [37,38]. We do not recommend a single bolus injection of ACh, to avoid severe complications. Coronary arteriography was performed when either ST-segment changes and/or chest pain occurred, or 1–2 min after the completion of each injection. Intracoronary injection of ACh into the responsible vessel is not performed if coronary artery spasm occurred spontaneously during coronary angiography. When an induced coronary spasm did not resolve spontaneously within 3 min after the completion of ACh injection or when hemodynamic instability occurred as the result of coronary spasm, 2.5–5.0 mg of nitrate was injected into the involved vessel. During the study, arterial blood pressure and an ECG are continuously monitored on an oscilloscope. A standard 12-lead ECG is recorded every 30 s. We recommend performing test shots at about 30-s intervals with a small amount of contrast medium during ACh testing, if necessary. We also recommend trying to perform coronary angiography before coronary spasm with complete obstruction is induced by pharmacologic agents. Moreover, ECG changes should be checked without administration of contrast medium or ACh or saline into the responsible vessel for at least 30–60 s. We should report ACh test negative but not negative of coronary spasm when intracoronary injection of ACh dose does not provoke spasm. Ong et al. reported ACh testing without pacemaker insertion [39,40]. However, we performed ACh testing with temporary pacemaker insertion in all patients. Indication and exclusion criteria of ACh test We also mentioned the indication and exclusion criteria of ER test in the former section. We cited all the same criteria during the ACh testing. The ACh spasm provocation test is not performed if patients had severe asthmatic bronchioles. According to the JCS guidelines [13], ACh spasm provocation test during coronary angiography performed in patients in whom VSA is suspected based on symptoms, who have not been diagnosed with coronary spasm by non-invasive evaluations, is classified as Class I. In contrast, in patients without symptoms suggestive of VSA, ACh

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spasm provocation test is classified as Class III. However, we have performed ACh spasm provocation tests except for patients with the above exclusion criteria as much as possible when suspecting coronary artery spasm, because coronary artery spasm may be present irrespective of atypical or silent symptoms. Advantages and disadvantages of ACh test The pharmacological effect of ACh is short compared with the effect of ER. The administration of nitrates to relieve provoked spasm on the first attempt artery is significantly higher in ER testing than in ACh tests [6.8% (76/1114) vs. 2.0% (31/1546), p < 0.001] [41]. In patients highly suspected of VSA with multiple spasm, we recommend the ACh tests first, and if positive spasm is not obtained, we perform ER test next. In contrast, in patients with chronic kidney disease, we recommend the intracoronary ER tests or saving ACh testing instead of the standard incremental ACh tests because of the adverse effect of using contrast medium. Considering the radiation exposure, we recommend the ER tests instead of performing the ACh tests. The radiation exposure during ACh testing is approximately two or three times higher than that of ER tests because of multiple procedures of ACh testing. Incidence of provoked spasm by ER and ACh tests As shown in Table 4, the frequency of provoked spasm by the intravenous injection of ER was significantly lower than that by the intracoronary administration of ER and Ach [42–45]. The frequency is approximately 2.5-fold higher when performed by the intracoronary administration of pharmacologic agents compared with that by unselective methods. However, there was no difference concerning the incidence of provoked spasm between ER and Ach [46]. Recently, Ong et al. reported that the provoked spasm frequency in even Caucasian white patients by performing ACh tests was similar to the incidence in Japanese patients [24]. If Caucasian cardiologists performed ACh tests routinely in the cardiac catheterization laboratory, we may understand that coronary artery spasm has no borders or no racial differences as a real truth. Asian cardiologists have been interested in performing

Table 4 Comparisons of provoked spasm frequency among the past studies. Bertrand et al. [41]

Nosaka et al. [42]

Sueda et al. [44]

Sueda et al. [43]

Ong et al. [24]

Year Study country (race) Sample size Male Methodology Dose

1982 French (Caucasian) 1089 – Intravenous ER Methergine 0.4 mg

1987 Japan (Japanese) 3000 1785 (59.5%) Intravenous ER ER 0.05–0.4 mg

Angina at rest Angina on effort Angina on effort and rest Myocardial infarction Atypical chest pain Valvular heart disease Dilated cardiomyopathy Hypertrophic cardiomyopathy After PCI Other Ischemic heart disease Non-ischemic heart disease Lesion 75% Lesion <75% Multiple spasm Over all

38% 4.3% 13.8% 15.0% 1.2% 2.0% 0% – – – 20.1% 1.3% 15.6% 9.5% 7.5% 12.3%

21% 18.3% 28.6% 22.9% 1.2% 4.8% 2.4% 9.5% – 2.5% 22.4% 2.6% 33.1% 7.5% 19.3% 12.8%

2004 Japan (Japanese) 596 369 (61.9%) Intracoronary ER RCA (40 mg) LCA (64 mg) 55.5% 27.7% 46.3% 35.6% 0.9% 16.7% 7.7% 14.3% 43.9% 3.9% 43.3% 3.7% 42.8% 24% 24.3% 29.0%

1999 Japan (Japanese) 685 477 (69.6%) Intracoronary ACh RCA (20/50/80 mg) LCA (20/50/100 mg) 66.9% 33.8% 49.0% 37.6% 4.8% 12.5% 3.4% 19.0% 31.3% 11.4% 45.7% 9.1% 35.9% 30.8% 29.0% 32.3%

2014 Germany (Caucasian) 847 362 (42.7%) Intracoronary ACh RCA (80 mg) LCA (2/20/100/200 g) 32.4% 32.4% 34.5% 41.5% 0% 0% 0% 0% 0% 0% 100% 0% 0% 100% – 33.4%

ER, ergonovine; ACh, acetylcholine; PCI, percutaneous coronary intervention.

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spasm provocation tests for approximately 30 years, while the majority of Caucasian cardiologists might have been little interested in the existence of coronary artery spasm. Complications Serious major complications including death were reported by the intravenous injection of ER [47,48]. However, no irreversible complications were observed by the intracoronary administration of ER. Selective ER test is safer than the intravenous injection of ER. Considering the occurrence of refractory spasm induced by ER, we recommend the selective spasm provocation test instead of unselective test. In our 1114 ER experiences, we had four major complications including two ventricular fibrillations and two ventricular tachycardias, which required direct current to recover sinus rhythm in two patients. However, no irreversible complications were recognized in our experiences. In contrast, Ong et al. reported that the complication rate of intracoronary ACh test was low. However, we experienced 28 major complications [1.8% (28/1546)] when performing intracoronary ACh tests. We administered the ACh into the responsible vessels for 20–30 s, whereas Ong et al. administered the ACh into the responsible vessels over 3 min without temporary pacemaker insertion. We routinely inserted the temporary pacemaker in all ACh tests. Moreover, we performed ACh spasm provocation tests on both coronary arteries in almost all patients, whereas Ong et al. performed ACh tests on both coronary arteries in only a third of the patients. Recently, Isogai et al. reported that the ACh spasm provocation tests were associated with a higher rate of serious cardiac complications than the ER tests from the analysis of 21512 patients in the diagnosis procedure combination database in Japan [0.9% (96/10628) vs. 0.4% (45/10884), p < 0.001] [49]. Serious major complications during ACh tests were higher than those of ER tests, but not significantly in our experience [0.9% (14/1546) vs. 0.4% (4/1114), ns], because our sample size was small. However, we had no irreversible complications during ACh and ER spasm provocation tests [50]. Difference between ACh and ER tests There are few reports concerning the provoked spasm between ER and ACh in the same patients [51–53]. Different mediators may have the potential of different coronary responses. In our experience, spasm provoked by intracoronary injection of ER is focal and proximal, while intracoronary administration of ACh provoked spasm distally and diffusely. Moreover, concordance of both provoked spasm sites and spasm configurations in the same

coronary artery was just 13% of vessels [53]. In our 461 patients in whom we performed both ER and ACh tests, the provoked spasm frequency by ACh test was significantly higher than that by ER tests [ACh: 39.3% (181/461) vs. ER: 25.8% (119/461), p < 0.001]. In particular, ACh is supersensitive in female patients (ACh: 96.7% vs. ER: 32.8%, p < 0.001) [54]. We should recognize that ER is remarkably different from ACh as a spasm provocation agent. In contrast, as shown in Table 5, Suzuki et al. reported that the positive spasm by ACh testing was 82%, while the positive provoked spasm by ER test was 100% [51]. According to the report by Kanazawa et al., the intracoronary injection of ACh provoked positive spasm in 80%, whereas the intracoronary administration of ER induced positive spasm in 65% [52]. However, there were no differences concerning the provoked spasm between ACh and ER tests in the small studies including our initial report. However, we should investigate the coronary response between the ER test and the ACh test in worldwide future studies. Investigation of microvascular dysfunction in patients with VSA For the evaluation of coronary microvascular function in patients with VSA after the diagnosis by the administration of intracoronary ACh/ER and intravenous ER, a Doppler flow guidewire was employed [55–57]. Akasaka et al. employed the Doppler guidewire for the evaluation of microvascular function after the intravenous administration of ER [55], while Teragawa investigated the microvascular function by using a 0.0014 Doppler flow guidewire after the intracoronary ACh and ER [56]. However, the conflicting results regarding the microvascular dysfunction in patients with VSA have been reported. Recently, Yamanaga et al. reported the impaired endothelial-independent microvascular relaxant function in patients with VSA by using a Combowire (Volcano Corp., Rancho Coldova, CA, USA) equipped with a Doppler velocity probe and a pressure sensor after the diagnosis with the intracoronary administration of Ach [57]. Although a Combowire is superior to a Doppler flow guidewire, it is controversial which pharmacological agent is the best selection in patients with VSA for the evaluation of mlicrovascular function. Further study is necessary for the investigation/evaluation of microvascular dysfunction in patients with VSA. Comparison with international group [Coronary Vasomotion Disorders International Study Group (COVADIS)] Table 6 shows the comparisons of indications for spasm provocation testing between the JCS guidelines and the COVADIS group [13,58,59]. The indications for provocative spasm testing of the COVADIS group are similar to those of the JCS guidelines.

Table 5 Comparisons of ACh and ER tests in the same patients.

Year Patient number Diagnosis Male/female Age (years) Procedures Dose of ACh (mg) Dose of ER (mg) Administration interval (min) Organic stenosis (>75%) Angiographical definition of positive spasm (%) Positive spasm by ACh test Positive spasm by ER test Positive spasm by Sero test

Suzuki et al. [50]

Kanazawa et al. [51]

Sueda et al. [52]

1992 11 VSA 9/2 54  9 ACh ! ER 25/50/100 1/5/10/30 120? 2 >99% 82% (9/11) 100% (11/11)

1997 20 VSA 15/5 57  10 ACh ! Sero ! ER 50/100 40 3–5 0 90% 80% (16/20) 65% (13/20) 65% (13/20)

2003 171 IHD 106/65 62  10 ACh ! ER 20/50/80/100 40/64 10 0 >99% 33% (56/171) 32% (54/171)

VSA, vasospastic angina; IHD, ischemic heart disease; ACh, acetylcholine; Sero, serotonin; ER, ergonovine.

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Table 6 Comparisons of indications for provocative spasm testing between JCS guidelines and COVADIS group. JCS guidelines

COVADIS group

Class I VSA is suspected based on symptoms, but in those who have not been diagnosed with coronary spasm by non-invasive evaluation

Class I (strong indication) History suspected of VSA without documented spontaneous episode especially if: Nitrate-responsive rest angina, and/or Marked diurnal variation in symptom onset/exercise tolerance, and/or Rest angina without obstructive coronary artery disease Acute coronary syndrome presentation in the absence of a culprit lesion Unexplained resuscitated cardiac arrest Unexplained syncope with antecedent chest pain Recurrent rest angina following angiographically successful PCI Class IIa (good indications) Invasive testing for non-invasive diagnosed patients unresponsive to drug therapy

Class IIa Patients who have been diagnosed with coronary spasm by non-invasive evaluation, and medical treatment is ineffective or insufficiently effective Class IIb Patients who have been diagnosed with coronary spasm by non-invasive evaluation, and medical treatment has been proven to be effective

Class IIb (controversial indications) Documented spontaneous episode of variant angina

Class III Emergent coronary angiography in patients with acute coronary syndrome High risk of suffering life-threatening complications induced by coronary spasm (LMT/MVD including obstructive lesions) Severe cardiac dysfunction or CHF (Class IIb if may be consequence of vasospasm) Patients without symptoms suggestive of VSA

Invasive testing for non-invasive diagnosed patients responsive to drug therapy Class III (contra-indications) Emergent acute coronary syndrome Severe fixed multivessel CAD including LMT artery stenosis Severe myocardial dysfunction (Class IIb if symptoms suggestive of vasospasm) Patients without any symptoms suggestive of VSA

JCS, Japanese Circulation Society; COVADIS, coronary vasomotion disorders international study group; VSA, vasospastic angina; PCI, percutaneous coronary intervention; CAD, coronary artery disease; LMT, left main trunk; MVD, multivessel disease; CHF.

Pharmacological spasm provocation tests are defined as Class I in the COVADIS recommendation, whereas ESC and ACC/AHA gave spasm provocation testing as Class IIa or Class IIb, respectively. The COVADIS group recommended that the provocative spasm testing should be performed in patients with unexplained syncope with antecedent chest pain and unexplained resuscitated cardiac arrest as Class I. According to the report of COVADIS group, the gold standard method for provocative spasm testing involves the administration of a provocative stimulus (typically intracoronary

ACh but alternatively intracoronary or intravenous ER) during invasive coronary angiography with the monitoring of patient symptoms, ECG, and angiographic documentation of coronary spasm. However, in these reports [58,59], we could find neither the dose of ACh/ER nor detailed procedures. The JCS guidelines do not recommend the intravenous ER tests due to unselective method, whereas the COVADIS group is allowed to employ the intravenous ER method as well as the intracoronary ER testing. The COVADIS group summarized the international standardization of diagnostic

1) Single method ACh test LCA (20/50/100/200 µg) RCA (20/50/80 µg)

ER test LCA (64 µg) RCA (40 µg)

2) Supplementary method ACh test

ER test

LCA (20/50/100/200 µ g) RCA (20/50/80 µg)

LCA (64 µg) RCA (40 µg)

ER test

ACh test

LCA (64 µg) RCA (40 µg)

LCA (20/50/100/200 µg) RCA (20/50/80 µg)

3) Sequential method ACh test

ER test

Adding ACh after ER test

LCA (20/50/100/200 µg) RCA (20/50/80 µg)

LCA (64 µg) RCA (40 µg)

LCA: ER (64 µg)+ACh (100 or 200 µg) RCA: ER (40 µg)+ACh (50 or 80 µg)

Fig. 1. Recommendation schema for pharmacological spasm provocation test. ACh, acetylcholine; ER, ergonovine; LCA, left coronary artery; RCA, right coronary artery.

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criteria for VSA. However, this statement has no detailed procedures of invasive pharmacological spasm provocation tests.

Acknowledgments

ACh and ER tests hereafter

We acknowledge the helpful comments of Professor Yuji Shigematsu, MD, Professor Mareomi Hamada, MD, Professor Jitsuo Higaki, MD, and Professor Kunio Hiwada, MD.

Spasm provocation tests have self-limitations to document coronary artery spasm during daily life. In the past reports, ST elevation was reproducible in some patients with variant angina by the administration of ACh or ER. However, we now employ the ER and ACh spasm provocation tests in patients with not only variant angina but also non-variant angina. In patients with low disease activity, we may not obtain positive spasm even by performing either single ER or ACh test. As shown in Fig. 1, we recommend the supplementary use of pharmacological spasm provocation tests if patients had no provoked spasm by the single ACh or ER test. Moreover, if we could not obtain the typical positive spasm in patients with strongly suspected coronary spasm by the supplementary method, we may select to perform the sequential spasm provocation tests: first, ACh test, second, ER tests, and last, adding intracoronary ACh after ER tests [60]. Goto et al. also reported the usefulness of adding intracoronary injection of ACh following the intravenous infusion of ER when intravenous administration of ER 0.4 mg showed negative spasms [61]. We also reported that the sensitivity and specificity of the combined sequential spasm provocation tests was more than 90%. Hereafter, if we could not obtain positive spasm in patients with strongly suspected coronary spasm, we should perform the supplementary use of ER and ACh and combined sequential tests. By performing the above tests, we will obtain the real truth in the clinic [62]. However, we should also take care of the pseudopositive response during the supplementary and sequential methods. Conclusions We could perform the pharmacological spasm provocation tests without irreversible complications. Prior ACC/AHA guidelines support limited use of the pharmacological spasm provocation testing for spasm; however, current guidelines do not address the provocative testing [63]. We hope that ACC/AHA guidelines and ESC guidelines give spasm provocation testing a Class I indication similar to the JCS guidelines and the COVADIS group. We should perform the pharmacological spasm provocation tests routinely when we undertake coronary angiography as much as possible. If we performed the routine pharmacological spasm provocation tests in the cardiac catheterization laboratory, we will learn many things in the future. The era in which cardiologists investigate the presence of coronary artery stenosis in the cardiac catheterization laboratory has passed, because we could obtain the clear coronary trees by using other modalities such as coronary computed tomography or magnetic resonance imaging. Cardiologists are now in the next stage in which they should strictly diagnose patients without significant stenosis and medicate these patients appropriately, because patients without obstructive coronary artery disease are not always normal. Patients with normal coronary arteriogram may have variant angina, severe triple vessel spasms, or microvascular spasm/angina. These states may lead to sudden cardiac death/acute coronary syndrome or poor prognosis in the future. Funding None. Conflicts of interest The authors state that there are no conflicts of interest.

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