Gender differences in sensitivity of acetylcholine and ergonovine to coronary spasm provocation test

We examined the sex difference concerning the coronary artery response between ACh and ER in this study. We already reported the difference of coronary response between acetylcholine (ACh) and ergonovine (ER). We performed both ACh and ER tests of 461 patients (male 294 patients, female 167 patients, mean age 64.4 ± 11.3 years) during 23 years. Positive coronary spasm was defined as >99 % transient luminal narrowing with usual chest pain and/or ischemic ECG changes. Firstly, ACh was administered in incremental doses of 20/50/(80) μg into the RCA and 20/50/100/(200) μg into the LCA over 20 s. Secondly, ER was administered in a total dose of 40 μg into the RCA and of 64 μg into the LCA over 2–4 min. Intracoronary injection of ACh and ER provoked spasm in 221 patients consisting of 160 male patients and 61 female patients. In female patients, the spasm provoked by ACh was almost perfect except in two patients (59 patients, 96.7 %), while ER provoked spasm in only 20 patients (32.8 %). In male patients, provoked spasm by ACh (129 patients, 80.6 %) was significantly higher than ER (97 patients, 60.6 %). As a spasm provocation test, ACh is more sensitive than ER in both sexes and especially in females. We may select two pharmacological agents by sex differences to provoke coronary artery spasm in the cardiac catheterization laboratory in the future.     

Complete definite positive spasm on acetylcholine spasm provocation tests: comparison of clinical positive spasm

In the clinical grounds, patients with ≥90 % luminal narrowing during acetylcholine (ACh) testing had variable response. We investigated ischemic findings and chest symptoms in patients with ≥90 % luminal narrowing when performing ACh tests, retrospectively. We performed 763 ACh tests over 13 years (2001–2013). We analyzed chest symptoms and positive ischemic ECG changes during ACh tests. More than 90 % luminal narrowing was found in 441 patients (57.8 %) including 355 patients in the right coronary artery (RCA) and 363 patients in the left coronary artery (LCA). Chest symptom was observed in 386 patients (87.5 %) including 293 patients in the RCA and 304 patients in the LCA. ST elevation was found in 161 patients including 110 in the RCA and 85 patients in the LCA, while ST depression was recognized in 146 patients including 119 patients in the RCA and 117 patients in the LCA. Three quarter of patients with ≥90 % luminal narrowing had significant ischemic ECG changes, whereas two-third of patients with ≥90 % luminal narrowing complained usual chest pain accompanied with significant ischemic ECG changes. Unusual chest symptom was complained in 7.3 % patients with ≥90 % luminal narrowing. Neither chest symptom nor ECG changes were found in 30 patients (6.8 %) with ≥90 % luminal narrowing. A third of these patients had ischemic findings on non-invasive tests before catheterization and six patients had subtotal or total occlusion. We should realize some limitation to define positive coronary spasm based on the ischemic ECG change and chest symptom during ACh tests.     

Shock during spasm provocation tests with acetylcholine: four case reports

Four patients suffered shock during the spasm provocation test with acetylcholine. An 84-year-old man with acute coronary syndrome was treated with stent implantation in the mid left anterior descending artery. Before discharge, acetylcholine test demonstrated coronary spasm in both the proximal left anterior descending artery and proximal left circumflex artery. A 61-year-old woman was admitted to the hospital because of recurrent rest and effort chest pain. Coronary arteriography showed no significant stenosis but shock was observed by intracoronary injection of acetylcholine due to diffuse severe coronary vasospasm in the proximal left anterior descending artery and left circumflex artery. Shock occurred in 4 of 1110 (0.36%) consecutive acetylcholine tests. Coronary spasm was gradually relieved and recovered from shock by the intraarterial administration of small amounts of norepinephrine and isosorbide dinitrate. Although the acetylcholine spasm provocation test is safe and reliable, care is required even during a selective procedure.     

Major complications during spasm provocation tests with an intracoronary injection of acetylcholine

This study sought to clarify major complications associated with acetylcholine testing. Serious major complications, such as sustained ventricular tachycardia, shock, and cardiac tamponade were determined in 4 of 715 patients (0.56%), but no cases of death or irreversible complications occurred. The spasm provocation test using acetylcholine should be performed carefully, although it is considered a safe and reliable method.     

New combined spasm provocation test in patients with rest angina: intracoronary injection of acetylcholine after intracoronary administration of ergonovine

The incidence of provoked coronary spasm with the standard single spasm provocation test has been relatively low in patients with rest angina. The present study examined the clinical usefulness of a newly designed spasm provocation test, an intracoronary injection of acetylcholine (ACh) following an ergonovine (ER) test, in patients with rest angina who demonstrated low disease activity and atypical chest pain. Triple sequential spasm provocation tests were performed in 24 patients with atypical chest pain who had no ischemia and in 40 patients with rest angina who had distinct ischemia. Initially, an ACh test (20-100 microg) and then an ER test (40-64 microg) were performed and then, if no spasm was provoked, an intracoronary injection of ACh was given after the ER test to evaluate coronary spasm. Coronary spasm was defined as total or subtotal occlusion. In the 24 patients with atypical chest pain, no spasm was provoked by intracoronary injection of either ACh or ER, but coronary spasms were induced in 2 patients using the new method, with the remaining 22 not experiencing spasm (specificity of new method, 92%). In the 40 patients with rest angina, intracoronary injection of ACh induced coronary spasm in 22 patients (group I) and 6 (group II) demonstrated spasm with intracoronary injection of ER. Coronary spasm was not induced by either the ACh test or the ER test in 12 patients (group III). The intracoronary administration of ACh after the ER test provoked spasm in 11 of 12 patients. Diffuse spasms were provoked in 10 of 11 patients. In patients with rest angina, the frequency of chest pain attacks in 1 month experienced by patients in group III (0.8+/-0.8) was significantly lower than that of patients in group I (7.0+/-5.3, p<0.01) or II (3.5+/-2.3, p<0.05). No serious or irreversible complications related to this new combined method were observed. In conclusion, this method was safe and reliable for the induction of coronary spasm in patients with rest angina who may have low disease activity.     

Oesophageal spasm and angina : diagnostic value of ergometrine (ergonovine) provocation

Oesophageal spasm can be difficult to distinguish from cardiacpain. Ergometrine (ergonovine) provocation with oesophagealmanomelry offers a useful diagnostic test.     

Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine

BACKGROUND AND OBJECTIVES: There have been few studies comparing the clinical usefulness for the induction of coronary artery spasm (CAS) between acetylcholine (ACh) and ergonovine (ER). This study is designed: (1) to examine the duration of effect after intracoronary injection of ACh on the responsible vessels using a 0.014 inch, 15 MHz Doppler guide wire, and (2) to evaluate the efficacy of two pharmacological agents, ACh and ER, for the induction of CAS in patients with <50% stenosis in the cardiac laboratory. METHODS: Phasic coronary flow velocity patterns were recorded at rest and during ACh tests in 22 patients with normal or near-normal coronary arteries. The tip of the guide wire was placed on the proximal right coronary artery (RCA) and mid-left anterior descending artery. We measured the time required to baseline level of average peak velocity after intracoronary injection of ACh. We performed selective intracoronary administration of both ER and ACh in the same 171 patients (106 men, 65 women, mean age of 62+/-10 years) with <50% stenosis. Under no medication, ACh was injected first in incremental doses of 20, 50, and 80 microg into the RCA and of 20, 50, and 100 microg into the left coronary artery (LCA). Ten minutes later, ER was administered at 10 microg/min for four minutes for a maximal dose of 40 microg on the RCA and at 16 microg/min over four minutes for a total dose of 64 microg on the LCA. Positive spasm was defined as > or =99% luminal narrowing. RESULTS: The time-averaged peak velocity returned to baseline after intracoronary injection of ACh within 10 minutes in all 120 procedures, consisted of 19 with positive spasm (RCA (n=10): 245+/-33 s; LCA (n=9): 351+/-187 s) and 101 with negative spasm (RCA (n=48): 155+/-62 s, LCA (n=53): 248+/-106 s). In the overall results, there was no difference concerning the incidence of provoked spasm between the two pharmacological agents (ACh: 33% versus ER: 32%, NS). Coronary spasms were induced by either pharmacological agent in 134 vessels. Concordance in this study was 94% in all vessels, whereas the remaining 6% of vessels were different from each other. The non-concordance rate of the right coronary artery was significantly higher than that of the left coronary artery (10% versus 4%, p<0.01). However, ER provoked more focal spasms, whereas ACh provoked more diffuse and distal spasms, compared with each other. Seventy-four (55%) of the 134 vessels had coronary spasms in the same coronary arteries. Concordance of both provoked spasm sites and spasm configurations in the same coronary artery was observed in only 18 (13%) vessels. No serious or irreversible complications were observed during the two sequential tests. CONCLUSIONS: As a spasm provocation test, there were no differences between ACh and ER. We recommend the supplementary use of these two pharmacological agents for the induction of CAS in the cardiac laboratory, if available.     

Induction of coronary artery spasm by intracoronary acetylcholine: comparison with intracoronary ergonovine.

To investigate the mechanism of coronary spasm, we compared the action of acetylcholine with that of ergonovine in 11 patients with vasospastic angina (group 1) and in 15 patients with chest pain (group 2). Coronary arteriography was performed immediately after the patients received intracoronary injections of titrated increments of each agent. In the patients in group 1 occlusive or near-occlusive (99% luminal narrowing) coronary spasm associated with angina and ischemic electrocardiographic ST changes was noted in nine of 11 patients receiving acetylcholine and in all 11 patients receiving ergonovine. The region and the degree of the most severe coronary spasm on coronary arteriograms evoked by the two agents were the same in nine of the 11 patients in group 1. In the other two patients in group 1, spontaneous focal coronary spastic stenosis in the baseline coronary arteriogram was relieved by the intracoronary injection of acetylcholine, and a focal coronary occlusive spasm in the same region was induced repeatedly by the subsequent intracoronary injection of ergonovine (paradoxic phenomenon). In contrast, occlusive or near-occlusive coronary spasm was not induced by either agent in any patient in group 2. These results suggest that the two provocative tests for coronary spasm that involve acetylcholine and ergonovine are clinically useful in the diagnosis of vasospastic angina, but testing with intracoronary ergonovine is needed when a spontaneous focal coronary spasm is relieved by the intracoronary injection of acetylcholine. The results also indicate that in many patients with vasospastic angina, nonspecific hypersensitivity to acetylcholine or ergonovine in a definite region of the coronary arteries generally plays an important role in the induction of coronary spasm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Variability of electrocardiographic responses to repeated ergonovine provocation in variant angina patients with coronary artery spasm

We reviewed our experience with serial ergonovine provocative tests for coronary artery spasm (CAS) in ten variant angina patients with angiographically proved CAS. Of the 26 ergonovine tests performed in the ten patients, only four patients exhibited reproducible ECG response to ergonovine. The remaining six patients had variable and unpredictable ECG responses to ergonovine. All patients were in an active phase of their disease. The variability of ST segment directional response to ergonovine is considered to be on the basis of disparate sensitivity of the coronary circulation to intravenous ergonovine. Because of this variable response, the ECG response alone should not be considered as the standard indicator for CAS presence but should be utilized with other hemodynamic and angiographic criteria.     

Reduction of coronary blood flow during coronary artery spasm occurring spontaneously and after provocation by ergonovine maleate

A 50-year-old man suffering from recurrent chest pain accompanied by transient ST-segment elevation developed spasm of the left anterior descending coronary artery after receiving ergonovine maleate. During spontaneous chest pain, thermodilution coronary sinus blood flow fell from 96 ml/min to 46 ml/min, while the coronary sinsu arteriovenous oxygen difference widened from 9.82 volumes percent to 11.3 volumes percent. During spontaneous relief of pain, coincident with resolution of the ST-segment changes, coronary sinus blood flow gradually rose to 135 ml/min, while coronary sinus arteriovenous oxygen difference narrowed to 6.82 volumes percent. Similar aterations in coronoary sinus blood flow accompanied chest pain provoked by ergonovine maleate. A thallium-201 scan confirmed a perfusion defect in the distribution the left anterior descending coronary artery. Thus, coronary artery spasm can produce a marked deficity in coronary blood flow that is associated with increased myocardial oxygen extraction; release of spasm creates a hyperemic response.     

Long-term study of recurrent vasospastic angina using coronary angiograms during ergonovine provocation tests.

Chronologic changes of coronary spasm were examined by repeated ergonovine provocation tests during angiography. A total of 322 patients who had variant angina without severe atherosclerosis demonstrated a positive response to the first test. Ninety of these patients had recurrent variant anginal symptoms after an angina-free period of 38 +/- 12 months (mean +/- SD). Of these 90 patients, 76 (84%) had symptoms or electrocardiographic (ECG) findings similar to those of the first test. The initial 9 of these 76 patients underwent a second provocation test and showed coronary responses analogous to those on the first test. Of the 90 patients, 14 (16%) had different symptoms or ECG findings from those elicited at the first episode. All 14 patients again had a positive response to a second ergonovine test and the following angiographic changes were observed in the three major vessels between the two tests. Of the 21 vessels that had spasm on the first test, eight vessels (19%) did not have spasm on the second test. Of the 21 vessels that did not demonstrate spasm on the first test, 10 (24%) demonstrated spasm on the second test. In the present study it is concluded that the majority of patients with recurrent angina seemed to have consistency in the location of coronary spasm, while in some patients the fluctuation of coronary spasm was confirmed by two ergonovine provocation tests.     

Frequency of provoked coronary spasms in patients undergoing coronary arteriography using a spasm provocation test via intracoronary administration of ergonovine

There are no data concerning the incidence of provoked coronary arterial spasms via intracoronary administration of ergonovine (ER). This study sought to establish the incidence of spasms due to intracoronary injection of ER in Japanese patients who underwent coronary angiography. The subjects were 596 consecutive patients (369 men, mean age 64.2 +/- 10.3 years) who were studied with a selective ER test. ER was administered in total doses of 40 microg into the right coronary artery and 64 microg into the left coronary artery. A positive spasm was defined as a total or subtotal occlusion. Coronary vasospasms were determined in 173 patients (29.0%). Spasms occurred often in patients with ischemic heart disease (43.3%); during effort and rest in patients with angina (46.3%), exertional angina (27.7%), recent myocardial infarction (36.7%), healed myocardial infarction (34.1%), and especially in patients with rest angina (55.5%), but were relatively uncommon in patients with nonischemic heart disease (3.7%). The incidence of provoked coronary spasms in this study was 2.2-2.6 times higher than in previous reports with intravenous ER administration. More spasms were superimposed on significant atherosclerotic lesions than on nonfixed atherosclerotic lesions (42.8% vs 24.0%, p < 0.01). No serious or irreversible complications were observed in this study. In conclusion, intracoronary administration of ER was a safe and reliable test. Compared with Caucasian patients, in Japanese patients, coronary arterial spasms occurred 2-3 times more frequently with various cardiac disorders.     

Evaluation of adjunctive intracoronary administration of acetylcholine following intravenous infusion of ergonovine to provoke coronary artery spasm

A dilemma arises in patients with chest pain or other symptoms suggestive of coronary artery disease but without significant coronary artery stenosis or spasm even after the spasm provocation test by either ergonovine or acetylcholine. Incremental doses of intracoronary acetylcholine (up to 100 micrograms for left coronary artery and 50 micrograms for right coronary artery) were administered when intravenous infusion of ergonovine 0.4 mg showed negative results. A total of 39 patients were studied. Provocation test was performed because of chest pain suggestive of coronary artery disease (n = 19), atypical chest pain (n = 6), post balloon angioplasty status (n = 6), silent ischemia (n = 4), Adams-Stokes syndrome (n = 3), and dead-on-arrival (n = 1). Characteristics of chest pain indicated variant angina (n = 11), rest angina (n = 4), and effort angina (n = 4). No electrocardiographic evidence of ischemia was detected before this test in any patient. Spasm was induced in 23 patients (59.0%) with complete obstruction in 7 (30.4%), diffuse vasoconstriction (90-99%) in 14 (60.9%), and focal spasm in 2 (8.7%). The patients with chest pain showed the highest positive rate of 78.9%. Further, the patients with atypical chest pain and miscellaneous reasons also revealed positive rates of 33.3% and 42.9%, respectively. One ventricular tachycardia and 2 atrial fibrillations occurred but terminated spontaneously. This test is useful for detecting spasm in a variety of patients in whom intravenous ergonovine infusion fails to induce spasm.     

Importance of a second spasm provocation test: Four cases with an initial negative spasm provocation test

The spasm provocation test(SPT) is an important test in the diagnosis of vasospastic angina(VSA). In many cases, this test is performed as the gold standard test, and VSA is considered not present if the SPT is negative. However, some patients continue to experience chest symptoms despite a negative SPT. In this study, we report four cases in which SPT was repeated to evaluate chest symptoms despite the negative results of the first SPT. Two men in their 70 s, one woman in her 60 s, and one woman in her 70 s, all with chest symptoms, underwent a second SPT at 4, 3, 2, and 3 years, respectively, after the first SPT, which was negative. Three patients had positive results in the second SPT(75%). In conclusion, even when SPT is negative, the diagnosis of VSA should be made with clinical symptoms in consideration. In some cases, a second SPT may be required to confirm the diagnosis of VSA.     

Comparative performance of intravenous and intracoronary ergonovine provocation in vasospastic angina

BackgroundVasospastic angina is an infrequent underlying cause of angina and is under-diagnosed. Ergonovine provocation tests can be performed via intravenous or intracoronary injections. Although the safety profile of intracoronary injection has been well documented, no study has yet compared the intracoronary and intravenous injections regarding the positivity rate of the test.AimsThis study sought to compare the positivity rate of intravenous versus intracoronary injection of ergonovine in the diagnosis of vasospastic angina.MethodsBetween January 2010 and February 2018, 427 patients with suspected vasospastic angina underwent an ergonovine provocation test in 2 tertiary hospitals in France and were retrospectively included in this study. Injection was performed via the intravenous or the intracoronary route. The primary endpoint was the positivity rate of the test. Propensity score matching was used to account for confounding factors.Results427 patients were included in the study. Mean age was 60.3 (+/- 12.4) years. There were 247 (58%) females and 97 (23%) smokers. The intracoronary route was used in 199 (47%) patients. The indication for the test was acute coronary syndrome for 121 (28%). No rhythmic complications or deaths were reported. After propensity-matching, the baseline characteristics of the 2 groups (148 patients in each) were comparable. The positivity rate was 24% in the intracoronary group and 9% in the intravenous group (OR [95%CI]: 3.2 [1.6, 6.4]).ConclusionsIntracoronary injection of ergonovine is safe and associated with a positivity rate of the test three times higher compared to intravenous injection.     

Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine

This study examines the incidence of spasm by intracoronary injection of acetylcholine in Japanese patients who underwent coronary angiography. The subjects were 685 consecutive patients (477 men, mean age 63.2 +/- 7.5 years) who were studied with an acetylcholine test. Acetylcholine was injected in incremental doses of 20, 50, and 80 microg into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Spasm was defined as total or subtotal occlusion. Coronary vasospasm was determined in 221 patients (32.3%). Spasm occurred often during effort and rest in patients with angina (25 of 51, 49.0%), exertional angina (25 of 74, 33.8%), recent myocardial infarction (30 of 80, 37.5%), healed myocardial infarction (14 of 37, 37.8%), and especially in patients with rest angina (83 of 124, 66.9%), whereas spasm was relatively uncommon in patients with nonischemic heart disease (23 of 252, 9.1%). Spasm was superimposed on significant atherosclerotic lesions in 35.9% of patients as well as on nonfixed atherosclerotic lesions in 30.8% of patients. We conclude that >9% of Japanese patients may have coronary vasospasm with intracoronary injection of acetylcholine and recommend the provocation test for evaluating coronary vasospasm if coronary angiography is undertaken.     

Impact of low-dose aspirin on coronary artery spasm as assessed by intracoronary acetylcholine provocation test in Korean patients

High-dose aspirin has been reported to aggravate coronary artery spasm (CAS). However, it is unknown whether low-dose aspirin (LDA; 100mg) has deleterious impact on CAS. We assessed the impact of LDA on CAS induced by intracoronary acetylcholine (ACh) provocation test. A total of 2789 consecutive patients without significant coronary artery disease who underwent ACh test between November 2004 and March 2010 were enrolled. The patients were divided into two groups: the aspirin group taking LDA before ACh test (n=221) and the no aspirin group not taking aspirin (n=2568). At baseline, the prevalence of old age, diabetes mellitus, hypertension, and hyperlipidemia were higher in the aspirin group. During the ACh test, the incidence of significant CAS, ischemic chest pain, as well as severe and multivessel spasm was higher in the aspirin group. The response rate to lower ACh dose was higher in the aspirin group. Multivariate analysis showed that the previous use of LDA was an independent predictor of CAS (adjusted odds ratio, 1.6, 95% confidence interval, 1.0-2.3; p=0.031). However, it is likely that the association of LDA and CAS that we have observed is not causal but may be hypothesis generating due to significant baseline differences. Further, male gender, old age, lipid-lowering drugs, baseline spasm, and myocardial bridge were independent predictors of CAS. LDA was more frequently associated with CAS and ischemic symptoms, as well as severe and multivessel spasm, suggesting the patients who have received LDA would require more intensive medical therapies and close follow up.