Intracoronary ergonovine testing among 505 consecutive Japanese patients with angina-like chest pain and unobstructed coronary artery disease.

Intracoronary ergonovine (ER) testing is useful for the detection of epicardial spasm (ES) and coronary microvascular spasm (CMS). We retrospectively analyzed the incidence of ES and CMS in consecutive Japanese patients with unobstructed coronary artery disease. From January 1991 to February 2019, we performed intracoronary ER testing of 1196 patients. Among these patients, a total of 505 consecutive patients (207 women, mean age 64 ± 11 years) who underwent first diagnostic angiography for suspected myocardial ischemia and had unobstructed coronary arteries (< 50%) were enrolled. Resting chest pain was reported by 229 patients, exertional chest pain was reported by 62 patients, exertional and resting chest pain was reported by 61 patients, and another chest symptom (not typical chest pain but suspected to be myocardial ischemia) was reported by 153 patients. ES was defined as ≥ 90% stenosis and usual chest symptoms and ischemic ECG changes, while CMS was defined as < 75% stenosis (no epicardial spasm) and usual chest symptoms and ischemic ECG changes. We performed intracoronary ER testing on both coronary arteries in 86% (432/505) of all subjects. Overall, ES was found in 82 patients (16%), whereas CMS was revealed in 12 patients (2%). In patients with ES, women made up 9%, and 70% of the patients had resting chest pain. In contrast, women composed 67% (8/12) of those with CMS, and 5 patients with CMS had another chest symptom. Ventricular fibrillation was observed in two patients who had sinus rhythm after thump version or cardiac resuscitation. However, we observed no irreversible complications during ER testing. CMS was recognized in only 2% of consecutive Japanese patients with unobstructed coronary artery disease by intracoronary ER testing, whereas ES was revealed in 16% of those patients. CMS was often observed in women.

Coincidence between spontaneous and inducible coronary spasm: acetylcholine test is clinically valued for diagnosing coronary spasm.

There is no report regarding the correlation between spontaneous documented coronary spasm and acetylcholine (ACh)-inducible spasm. We retrospectively analyzed the coincidence between angiographical spontaneous coronary spasm and ACh-inducible spasm in the same patients. We recruited 28 patients with 30 angiographical spontaneous coronary spasm in 6009 patients with diagnostic and follow-up coronary arteriography from Jan 1991 and Mar 2019 in the cardiac catheterization laboratory. We could perform intracoronary ACh testing in 19 patients with 20 vessels. ACh was injected in incremental dose of 20/50/100 µg into the left coronary artery and 20/50/80 µg into the right coronary artery. Positive spasm was defined as > 90% stenosis and ischemic ECG changes. Angiographical documented spontaneous coronary spasm was observed in 0.47% (28/6009) of patients with diagnostic and follow-up coronary angiography. Intracoronary administration of ACh reproduced 15 spontaneous coronary spasm and no provoked spasm was observed in the remaining 5 vessels due to the administration of nitroglycerine or under medications. Spasm-provoked sites by ACh tests and ACh-inducible spasm configurations were almost similar to spontaneous spasm. Coincidence of provoked spasm site (93.3% vs. 6.7%, p < 0.001) and spasm configuration (93.3% vs. 6.7%, p < 0.001) was markedly higher than discordance. Intracoronary ACh testing can reproduce spontaneous coronary artery spasm in 75% of vessels with almost similar sites and same morphological characteristics irrespective of the administration of nitroglycerine or vasodilators. ACh test is a reliable method to document coronary artery spasm in the clinic.

Coronary artery spasm-induced acute myocardial infarction in patients with myocardial infarction with non-obstructive coronary arteries.

Coronary artery spasm-induced acute myocardial infarction (CASIAMI) is one of the etiologies of myocardial infarction with non-obstructive coronary arteries (MINOCA). We retrospectively analyzed the incidence and clinical characteristics of Japanese patients with CASIAMI and non-obstructive coronary arteries. We experienced 62 patients with MINOCA (10 thrombosis, 7 unknown causes, and 45 CASIAMI) among 991 patients with suspected AMI. Pharmacological spasm provocation testing was performed in 37 patients. CASIAMI without obstructive coronary arteries was found in 4.5% of patients with suspected AMI and was observed in 73% of patients with MINOCA. Patients with CASIAMI were frequently males and had relatively small AMIs. Spontaneous spasm was recognized in 8 patients. We could reproduce provoked spasm in 37 patients with MINOCA, including 23 patients with multiple spasm. No patients died during the follow-up period. The clinical outcomes in patients with CASIAMI under optimal coronary vasodilators were satisfactory.

Pharmacological spasm provocation testing in 2500 patients: provoked spasm incidence, complications and cardiac events.

Pharmacological spasm provocation tests such as acetylcholine (ACh) and ergonovine (ER) had been performed in the clinic. We retrospectively analyzed the incidence of provoked spasm, complications during testing and the cardiac events after these tests. From January 1991 and October 2018, we performed pharmacological spasm provocation tests in 2500 patients: 1810 ACh tests, 1232 ER tests, 542 both tests, and 310 ACh added after ER tests. ACh was injected in incremental doses of 20/50/100/200 µg into the LCA and 20/50/80 µg into the RCA. ER was administered as a total dose of 64 µg into the LCA and 40 µg into the RCA. When adding ACh after ER, the total dose was 50/80 µg into the RCA and 100/200 µg into the LCA. Positive spasm was defined as ≥ 90% stenosis and usual chest pain or ischemic ECG changes. Mean follow-up duration was 47.5 ± 29.9 months. Overall, provoked positive spasm was found in 1095 patients (43.8%). The incidence of positive provoked spasm during ACh testing was significantly higher than that during other tests (ACh: 48.7% vs. ER: 28.9%, Both: 24%, ACh added after ER: 33.5%, p < 0.001). Multiple spasms were remarkably more frequent during ACh testing compared with the other 3 types of testing (ACh: 28.2% vs. ER: 7.4%, Both: 4.1%, ACh added after ER: 13.2%, p < 0.001). No death or acute myocardial infarction was observed, while major complications during ACh testing were significantly more frequent than during ER testing. Readmission due to recurrent angina pectoris in spasm-positive patients was remarkably more frequent than in spasm-negative patients. The incidence of sudden cardiac death, ventricular fibrillation, and acute coronary syndrome were not different between the spasm-positive and spasm-negative groups during the follow-up periods. We could perform all spasm provocation tests without any irreversible complications. All sequential spasm provocation tests were useful for documenting coronary spasm.

Clinical characteristics in patients with rest angina and hypoplastic right coronary artery.

Hypoplastic coronary artery disease is a rare congenital abnormality reported to be associated with myocardial infarction and sudden cardiac death. Provoked positive spasm in the left circumflex coronary artery (LCX) with pharmacological spasm provocation tests was remarkably lower than other coronary arteries. We sometimes encountered patients with rest angina and hypoplastic right coronary artery (H-RCA). Among 5953 patients with diagnostic and follow-up coronary arteriography, we found 93 patients (1.6%) with H-RCA. During the same period, we could perform spasm provocation tests in 564 patients with rest angina including 13 patients with H-RCA and 249 patients with effort angina including 10 patients with H-RCA. Pharmacological spasm provocation tests were performed in 51 of 93 patients including 34 patients with ischemic heart disease (IHD) and 17 patients with non-IHD. Provoked spasm incidence in patients with IHD was higher than in those with non-IHD but not significant (52.9% vs. 29.4%, p = 0.1114). Provoked positive spasm in the LCX in patients with rest angina and H-RCA was significantly higher than that in those without H-RCA (69.2% vs. 23.4%, p < 0.001). Provoked spasm on both left anterior descending artery and LCX in patients with rest angina and H-RCA was also remarkably higher than in those without H-RCA (53.8% vs. 3.1%, p < 0,001). There were no clinical differences between patients with and without H-RCA rest angina. Two-vessel spasm (61.5% vs. 0%, p < 0.01) and LCX-provoked spasm (69.2% vs. o%, p < 0.01) were significantly higher in patients with H-RCA and rest angina than that in those with H-RCA and effort angina. In patients with rest angina and H-RCA, LCX-positive spasm was significantly higher and these patients may have a potential of high disease activity in the clinic as a coronary spastic angina.

Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan.

OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.

Acetylcholine spasm provocation test by trans-radial artery and brachial vein approach.

BACKGROUND: Temporary pace maker is necessary because of transient block or bradycardia during the intracoronary acetylcholine spasm provocation tests based on the Japanese Circulation Society guidelines. OBJECTIVES: We examined the feasibility and safety of the acetylcholine spasm provocation test via the radial artery and brachial vein approach. METHODS: We tried to perform the acetylcholine spasm provocation tests in 252 patients via the radial artery and brachial vein approach procedures during 5 years. Acetylcholine was injected in incremental doses of 20/50/80 µg into the right coronary artery (RCA) and 20/50/100/200 µg into the left coronary artery (LCA). Back-up pacing rate was set at 40 beats/min. Positive spasm was defined as transient ≥90% luminal narrowing and ischemic electrocardiographic change or usual chest pain. RESULTS: The procedure success of radial artery and brachial vein access was 94.4% (238/252) and 93.3% (235/252), respectively. We performed 221 patients (87.7%) with acetylcholine tests by radial artery and brachial vein approach. We changed to the brachial approach due to the failures of radial artery access in 14 patients. We also changed to the femoral vein in 11 patients and internal jugular vein in two patients. Back-up pace maker rhythm was observed in 92.1% (232/252) of all study patients, while it was significantly higher in the RCA testing than that in the LCA tests (84.9% (191/225) vs. 52.2% (131/251), P < 0.001). No irreversible complication was found. CONCLUSIONS: We recommend the radial artery and brachial vein approach for safety and convenience when performing the acetylcholine spasm provocation tests.

Young Vasospastic Angina Patients Less Than 20 Years Old.

BACKGROUND: Japanese Circulation Society (JCS) guidelines do not include adolescents with coronary artery spasm.Methods and Results:We recruited 18 adolescents less than 20 years old with vasospastic angina (VSA): 11 were Japanese and 3 had chest symptoms for >12 months before admission. ST-segment elevation was observed in 11 patients and none of the 18 patients had a fixed stenosis. Spasm provocation tests were performed in 9 patients and two-thirds had multiple spasms; 6 suffered from acute myocardial infarction and ventricular fibrillation occurred in 2 patients; 1 patient died and the remaining 17 patents survived. CONCLUSIONS: Clinical status of adolescents with VSA was as severe as in adults with refractory VSA. Cardiologists should cooperate with pediatricians to diagnose and treat adolescents with VSA. There is a need to establish the additional issues for adolescents with coronary spasm in the JCS guidelines.

Differential incidence and morphology of provoked spasm between intracoronary acetylcholine and ergonovine testing: recommendation of supplementary use.

When cardiologists diagnose patients with coronary spastic angina, Japanese Circulation Society (JCS) guidelines recommend the intracoronary injection of acetylcholine (ACh) and ergonovine (ER) as class I. However, the pharmacological difference between ACh and ER is controversial in the clinic. We performed both ACh and ER tests in the same 528 patients during 26 years. We investigated the provoked spasm configuration, spasm site, and clinical characteristics of provoked spasm between ACh and ER, retrospectively. We defined positive spasm as ≥90% luminal narrowing. Provoked positive spasm was observed in 161 right coronary arteries (RCA) including 83 ACh just positive, 35 ER just positive, and 43 both positive. In contrast, positive spasm was documented in 172 left coronary arteries (LCA) including 94 ACh just positive, 28 ER just positive, and 50 both positive. ACh provoked spasm more distally and diffusely, while ER induced spasm more proximally and totally or focally in the RCA. In the LCA, ACh provoked spasm more proximally, whereas ER induced spasm more distally. ER testing after the negative ACh tests of RCA and LCA documented new positive spasms in 10.3% (35/340) and 7.4% (28/376), respectively. Coronary artery trees may each have a sensitive receptor on each segment. We recommend the supplementary use of ACh and ER to document coronary artery spasm in the cardiac catheterization laboratory.

Impact of pharmacological spasm provocation test in patients with a history of syncope.

Coronary artery spasm is involved in the pathogenesis of various cardiac disorders. We investigated patients with a history of syncope who underwent elective coronary angiography. We retrospectively analyzed 5781 consecutive patients who had diagnostic or follow-up angiography during a 26-year period. During this period, we found 95 patients with a history of syncope before elective coronary angiography. Pharmacological spasm provocation testing was performed in 64 patients with a history of syncope (<1 year). Positive pharmacological response was observed in 48 patients, while the remaining 16 patients had negative tests. Positive spasm was defined as a transient ≥90% narrowing with ischemic electrocardiographic changes. Among the 64 patients, definite coronary spastic angina (CSA) was found in 35 patients (54.7%) and suspected CSA was found in 13 patients (20.3%). Among the 35 patients with definite CSA, 22 patients (62.9%) had chest symptoms before syncope, but 13 (37.1%) had no chest symptom before syncope. No difference in clinical characteristics was observed between the two groups. Focal spasm during pharmacological spasm provocation tests was significantly higher in patients with chest symptoms than in those without chest symptoms before syncope (54.3 vs. 12.0%, p < 0.002). CSA was observed in 75.0% of patients with a history of syncope (<1 year). Thirteen patients with definite CSA had neither chest pain nor chest pressure before syncope. We should therefore investigate coronary artery spasm as a potential etiology in patients with a history of syncope.

Relationships between more than 90% coronary luminal narrowing induced by ergonovine provocation test and ECG ischemic change as well as chest symptoms.

In the clinic, patients with ≥90% luminal narrowing during ergonovine (ER) testing had variable response. We investigated ischemic findings and chest symptoms in patients with ≥90% luminal narrowing when performing ER tests, retrospectively. We performed 1210 ER tests over 26 years (1991-2016). We analyzed chest symptoms and positive ischemic ECG changes during ER tests. More than 90% luminal narrowing was found in 352 patients (29.1%) including 211 patients in the right coronary artery (RCA) and 217 patients in the left coronary artery (LCA). Chest symptom was observed in 290 patients (82.4%) including 162 patients in the RCA and 179 patients in the LCA. ST elevation was found in 154 patients including 98 in the RCA and 73 patients in the LCA, while ST depression was recognized in 81 patients including 38 patients in the RCA and 62 patients in the LCA. Two-third of patients with ≥90% luminal narrowing had significant ischemic ECG changes, whereas 60.5% of patients with ≥90% luminal narrowing complained usual chest pain accompanied with significant ischemic ECG changes. Unusual chest symptom was complained in 7.1% of patients with ≥90% luminal narrowing. Neither chest symptom nor ECG changes was found in 48 patients (13.6%) with ≥90% luminal narrowing. We should understand some limitation to diagnose positive coronary spasm during ER tests.

Differential Incidence and Morphology of Spasm According to Coronary Arterial Location by Intracoronary Ergonovine Spasm Provocation Testing.

BACKGROUND: We reported less provoked spasm in the left circumflex artery (LCX) by acetylcholine testing compared with the left anterior descending artery (LAD) and right coronary artery (RCA), so we investigated the clinical characteristics of provoked spasm in the LCX by ergonovine (ER) testing.Methods and Results:We retrospectively analyzed 1,185 consecutive cases of intracoronary ER testing during 25 years. Maximal ER dose was 64 µg into the left coronary artery (LCA) and 40 µg into the RCA. Positive spasm was defined as a transient ≥90% narrowing and usual chest symptoms or ischemic ECG changes. Positive provoked spasm was recognized in 347 patients (29.3%), including 207 RCA spasms, 166 LAD spasms, and 79 LCX spasms. Spasm was provoked in the LCX significantly less than in the other vessels (P<0.001). LCX-provoked spasm was obtained in 79 patients consisting of 16 patients (20.3%) with triple-vessel spasm, 38 patients (48.1%) with double-vessel spasm and 25 patients (31.6%) with single-vessel spasm. Less than 70% patients with LCX-provoked spasm had multiple spasms, whereas approximately 60% patients had single-vessel spasm in the RCA (64.3%) or LAD (59.6%). In 25 patients with LCX single-vessel spasm, 18 patients (72.0%) had a focal spasm. CONCLUSIONS: Under maximal ER dose of 64 µg into the LCA, LCX-provoked spasm occurred significantly less than spasm in the other vessels and less than 70% patients had multiple spasms.

The real world in the clinic before and after the establishment of guidelines for coronary artery spasm: a questionnaire for members of the Japanese Cine-angio Association.

We investigated the clinical situations and the present knowledge of Japanese cardiologists about coronary artery spasm before and after the establishment of guidelines for this condition in the real world. A questionnaire was developed regarding the number of cases of coronary angiography, percutaneous coronary intervention, and invasive/non-invasive spasm provocation tests before (2008) and after (2014) the establishment of the Japanese Circulation Society (JCS) guidelines for coronary artery spasm and the status of spasm provocation tests. The questionnaire was sent to members of the Japanese Cine-angio Association in 81 cardiology hospitals in Japan. The completed surveys were returned from 20 hospitals, giving a response rate of 24.7%. Pharmacological spasm provocation tests increased in 2014 and vasospastic angina and variant angina also increased in 2014 compared with 2008, but the increase was not significant. Non-invasive spasm provocation tests such as hyperventilation tests and cold stress tests decreased remarkably in 2014. Spasm provocation tests were initially performed in the left coronary artery was employed in just 30% of the hospitals. The majority of institutions did not perform the spasm provocation testing in patients with unknown causes of heart failure or in survivors of ventricular fibrillation. Although 40% of the hospitals were not satisfied with standard spasm provocation tests, the majority of the hospitals agreed that spasm provocation tests will be necessary in the future. In general, the JCS guidelines contributed to the widespread use of provocative testing for coronary artery spasm in the real world. However, some issues about spasm still remained in the clinic.

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.

Safety and optimal protocol of provocation test for diagnosis of multivessel coronary spasm.

We examined the safety of acetylcholine (ACh) and ergonovine (ER) tests retrospectively and investigated the optimal protocol of provocation test for diagnosis of multivessel coronary spasm. We performed 1546 ACh tests and 1114 ER tests during 23 years. ACh was injected in incremental doses of 20/50/80 µg into the right coronary artery (RCA) and of 20/50/100/200 µg into the left coronary artery (LCA) over 20 s. ER was administered in total doses of 40 µg into the RCA and of 64 µg into the LCA over 2-4 min. When a coronary spasm was induced and did not resolve spontaneously within 3 min after the completion of ACh/ER injection, or when hemodynamic instability due to coronary spasms occurred, 2.5-5.0 mg of nitrate was administered into the responsible vessel. To relive provoked spasm, it is necessary to administer nitrate in 31 cases by ACh and in 76 cases by ER (2.0 vs. 6.8 %, p < 0.01) before another vessel attempts. Multivessel spasms were often observed in LCA testing than in RCA testing on both agents [ACh: 78.6 % (11/14) vs. 11.8 % (2/17), p < 0.001, ER: 37.8 % (14/37) vs. 20.5 % (8/39), ns]. Even after the administration of nitrates, positive coronary spasm was obtained in 21.1 % by ACh and 52.9 % by ER tests on another coronary artery. No irreversible complications were recognized on both tests. We should firstly perform spasm provocation tests in the LCA and we may be able to diagnose another vessel spasm by performing the complete spasm provocation tests after the administration of nitrates to relieve provoked spasm in the first attempt.

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.

Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.

AIMS: Although nitrates are widely used as a concomitant therapy with calcium channel blockers (CCBs) for vasospastic angina (VSA), their prognostic contribution remains unclear. The present study aimed to examine the prognostic impact of chronic nitrate therapy in patients with VSA. METHODS AND RESULTS: A total of 1429 VSA patients (median 66 years; male/female, 1090/339) were enrolled. The primary endpoint was defined as major adverse cardiac events (MACE). The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates [e.g. nitroglycerin (GTN), isosorbide mono- and dinitrate] in 551 and nicorandil in 306. Calcium channel blockers were used in >90% of patients. During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates [11 vs. 8% at 5 years; hazard ratio (HR): 1.28; 95% confidence interval (CI): 0.72-2.28, P = 0.40]. Although nicorandil itself had a neutral prognostic effect on VSA (HR: 0.80; 95% CI: 0.28-2.27, P = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR: 2.14; 95% CI: 1.02-4.47; P = 0.044), particularly when GTN and nicorandil were simultaneously administered. CONCLUSIONS: Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates would have increased risk for cardiac events.

Maximal acetylcholine dose of 200 µg into the left coronary artery as a spasm provocation test: comparison with 100 µg of acetylcholine.

As a spasm provocation test of acetylcholine (ACH), incremental dose up (20/50/100 µg) into the left coronary artery (LCA) is recommended in the guidelines established by Japanese Circulation Society. Recently, Ong et al. reported the ACOVA study which maximal ACH dose was 200 µg in the LCA. We compared the angiographic findings between ACH 100 µg and ACH 200 µg in the LCA and also examined the usefulness and safety of ACH 200 µg in Japanese patients without variant angina. As a spasm provocation test, we performed intracoronary injection of ACH 200 µg after ACH 100 µg in 88 patients (55 males, 68.4 ± 11.7 years old) including 59 ischemic heart disease (IHD) patients and 29 non-IHD patients. Positive spasm was defined as >99 % transient stenosis (focal spasm) or 90 % severe diffuse vasoconstriction (diffuse spasm). Positive spasm by ACH 200 µg was significantly higher than that by ACH 100 µg (36 pts: 40.9 % vs. 17 pts: 19.3 %, p < 0.01). Diffuse distal spasm on the left anterior descending artery was more recognized in ACH 200 µg than in ACH 100 µg (30.7 vs. 13.6 %, p < 0.01). In 29 rest angina patients, positive spasm by ACH 200 µg (19 pts) was significantly higher than that by ACH 100 µg (7 pts) (65.5 vs. 24.1 %, p < 0.01). No serious irreversible complications were found during ACH 200 µg. Administration of ACH 200 µg into the LCA was safe and useful. We may reexamine the maximal ACH dose into the LCA.

Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.

AIMS: Provocation tests of coronary artery spasm are useful for the diagnosis of vasospastic angina (VSA). However, these tests are thought to have a potential risk of arrhythmic complications, including ventricular tachycardia (VT), ventricular fibrillation (VF), and brady-arrhythmias. We aimed to elucidate the safety and the clinical implications of the spasm provocation tests in the nationwide multicentre registry study by the Japanese Coronary Spasm Association. METHODS AND RESULTS: A total of 1244 VSA patients (M/F, 938/306; median 66 years) who underwent the spasm provocation tests were enrolled from 47 institutes. The primary endpoint was defined as major adverse cardiac events (MACEs). The provocation tests were performed with either acetylcholine (ACh, 57%) or ergonovine (40%). During the provocation tests, VT/VF and brady-arrhythmias developed at a rate of 3.2 and 2.7%, respectively. Overall incidence of arrhythmic complications was 6.8%, a comparable incidence of those during spontaneous angina attack (7.0%). Multivariable logistic regression analysis demonstrated that diffuse right coronary artery spasm (P < 0.01) and the use of ACh (P < 0.05) had a significant correlation with provocation-related VT/VF. During the median follow-up of 32 months, 69 patients (5.5%) reached the primary endpoint. The multivariable Cox proportional hazard model revealed that mixed (focal plus diffuse) type multivessel spasm had an important association with MACEs (adjusted hazard ratio, 2.84; 95% confidence interval, 1.34-6.03; P < 0.01), whereas provocation-related arrhythmias did not. CONCLUSION: The spasm provocation tests have an acceptable level of safety and the evaluation of spasm type may provide useful information for the risk prediction of VSA patients.