Positive Acetylcholine Provocation Test Research Articles

Relation of Vasoreactivity in the Left and Right Coronary Arteries During Acetylcholine Spasm Provocation Testing

The diagnosis of vasospastic angina (VSA) according to Japanese guidelines involves an initial intracoronary acetylcholine (ACh) provocation test in the left coronary artery (LCA) followed by testing in the right coronary artery (RCA). However, global variations in test protocols often lead to the omission of ACh provocation in the RCA, potentially resulting in the underdiagnosis of VSA. This study assessed the validity of the LCA-only ACh provocation approach for the VSA diagnosis and whether vasoreactivity in the LCA aids in determining further provocation in the RCA. A total of 273 patients who underwent sequential intracoronary ACh provocation testing in the LCA and RCA were included. Patients with a positive ACh provocation test in the LCA were excluded. Relations between vasoreactivity in the LCA and ACh test outcomes (positivity and adverse events) in the RCA were evaluated. In patients with negative ACh test results in the LCA, subsequent ACh testing was positive in the RCA in 23 out of 273 (8.4%) patients. Among patients with minimal LCA vasoconstriction (<25%), only 3.0% had a positive ACh test in the RCA, while the ACh test in the RCA was positive in 13.5% of those with LCA constriction of 25-90% (p=0.002). No major adverse events occurred during ACh testing in the RCA. In conclusion, for the VSA diagnosis, the omission of ACh provocation in the RCA may be clinically acceptable, particularly when vasoconstriction induced by ACh injection was minimal in the LCA. Further studies are needed to define ACh provocation protocols worldwide.

Thrombolysis in Myocardial Infarction Frame Count for Coronary Blood Flow Evaluation during Interventional Diagnostic Procedures.

Background and Objectives: An interventional diagnostic procedure (IDP), including intracoronary acetylcholine (ACh) provocation and coronary physiological testing, is recommended as an invasive diagnostic standard for patients suspected of ischemia with no obstructive coronary arteries (INOCA). Recent guidelines suggest Thrombolysis In Myocardial Infarction frame count (TFC) as an alternative to wire-based coronary physiological indices for diagnosing coronary microvascular dysfunction. We evaluated trajectories of TFC during IDP and the impact of ACh provocation on TFC. Materials and Methods: This was a single-center, retrospective study. Patients who underwent IDP to diagnose INOCA were included and divided into two groups according to the positive or negative ACh provocation test. Wire-based invasive physiological assessment was preceded by ACh provocation tests and intracoronary isosorbide dinitrate (ISDN). We evaluated TFC at three different time points during IDP; pre-ACh, post-ISDN, and post-hyperemia. Results: Of 104 patients, 58 (55.8%) had positive ACh provocation test. In the positive ACh group, resting mean transit time (Tmn) and baseline resistance index were significantly higher than in the negative ACh group. Post-ISDN TFC was significantly correlated with resting Tmn (r = 0.31, p = 0.002). Absolute TFC values were highest at pre-ACh, followed by post-ISDN and post-hyperemia in both groups. All between-time point differences in TFC were statistically significant in both groups, except for the change from pre-ACh to post-ISDN in the positive ACh group. Conclusions: In patients suspected of INOCA, TFC was modestly correlated with Tmn, a surrogate of coronary blood flow. The positive ACh provocation test influenced coronary blood flow assessment during IDP.

Layered Plaque in Organic Lesions in Patients With Coronary Artery Spasm.

BackgroundCoronary artery spasm plays a vital role in the pathogenesis of coronary plaques. We sought to investigate the plaque characteristics of co‐existing organic lesions in patients with coronary artery spasm in comparison to those without coronary artery spasm by intracoronary optical coherence tomography (OCT).Methods and ResultsWe included 39 patients who presented with a symptom suspected of coronary spastic angina and had an organic lesion, defined as ≥plaque burden of 50% assessed by OCT. Coronary artery spasm was diagnosed by positive acetylcholine provocation test, or by spontaneous spasm detected during coronary angiography. A total of 51 vessels with an organic lesion were identified. Of these, coronary artery spasm was observed in 30 vessels (spasm), while not in 21 vessels (non‐spasm). Organic lesions in the spasm vessels, compared with those in the non‐spasm vessels, had a higher prevalence of layered plaque (93% versus 38%, P<0.001), macrophages (80% versus 43%, P=0.016), and intraplaque microchannels (73% versus 24%, P<0.001), and lower prevalence of macrocalcification (23% versus 62%, P=0.009) as assessed by OCT.ConclusionsLayered plaque, macrophages, and intraplaque microchannels, were frequently observed in organic lesions in patients with coronary artery spasm. These findings suggest that coronary artery spasm induces local thrombus formation as well as active inflammatory response, therefore increasing the risk of rapid plaque progression and ischemic events in patients with coronary artery spasm.

Gender differences in factors associated with vasospastic angina

BackgroundVasospastic angina (VSA) is reportedly associated with several clinical characteristics such as smoking and high-density lipoprotein (HDL) cholesterol, in which gender differences are present. For instance, smoking rates among men are higher than those among women, and a normal range of HDL cholesterol differs across genders. However, their impact between men and women on VSA is unclear. MethodsA total of 797 patients (427 men and 370 women) undergoing intracoronary acetylcholine (ACh) provocation test to diagnose VSA were included. The positive ACh provocation test was defined as angiographic vasospasm accompanied by chest pain and/or ischemic electrocardiographic changes. Factors contributing to VSA across genders were evaluated by multivariable analyses. ResultsOf 797 patients, 414 (51.9%) had positive ACh provocation test. The incidence of positive ACh test was higher in men than in women (56.9% vs. 46.2%, p = 0.003). In the entire study population, current smoking and a lower HDL cholesterol level were determined as factors associated with VSA. In both men and women, an HDL cholesterol level was identified as a factor contributing to positive ACh test. ConclusionsAmong patients suspected for VSA, men as compared with women were more likely to have positive ACh provocation test. While current smoking and an HDL cholesterol level were associated with VSA in the entire study population, a lower HDL cholesterol level was determined as the only factor contributing to positive ACh test across genders, suggesting that HDL cholesterol plays important roles in the mechanism of VSA.

Relation Between Cancer and Vasospastic Angina.

IntroductionPatients with cancer have an increased risk of cardiovascular disease including ischemic heart disease and vice versa. Anticancer drugs and radiotherapy are known to contribute to endothelial injury and vasospasm. However, the relations between vasospastic angina (VSA) and cancer or its treatment are poorly investigated.MethodsA total of 786 patients underwent intracoronary acetylcholine (ACh) provocation tests to diagnose VSA. The positive ACh provocation test was defined as angiographic coronary artery spasm accompanied by chest pain and/or ischemic electrocardiographic changes. Patients were divided into active cancer, a history of cancer, and no cancer according to the status of malignancy. The impact of types of cancer, anticancer drugs, and radiotherapy on VSA was evaluated.ResultsOf 786 patients, 38 (4.8%) and 84 (10.7%) had active cancer and a history of cancer, respectively, and 401 (51.0%) were diagnosed as VSA. There was no significant difference in rates of positive ACh test among patients with active cancer, a history of cancer, and no cancer (39.5% vs. 57.1% vs. 50.9%, p = 0.20). Types of cancer and cancer treatment also had no impact on positive ACh provocation test.ConclusionsIn this cross-sectional observational study, we did not find an association of active and a history of cancer with the diagnosis of VSA. Anticancer treatment including chemotherapy and radiotherapy was not significantly associated with positive ACh provocation test.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01854-z.

Evaluation of traditional and non-traditional risk factors as predictive values for a positive acetylcholine provocation test in patients with ischemia and no obstructive coronary artery disease

Abstract Background Coronary vasomotor function disorders, such as microvascular angina (MVA) and vasospastic angina (VSA) can be diagnosed in three quarters of all patients with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA). Intracoronary acetylcholine provocation testing (Ach-test) is considered the gold standard for the assessment of VSA and MVA. Our aim is to identify the correlation between a positive Ach-test identifying an abnormal coronary vasomotor response and predictive traditional and non-traditional risk factors in patients with INOCA. Methods In this single centre retrospective cohort study, data from all patients who were referred for an Ach-test between 2002 and 2019 was collected. All patients underwent an invasive test with assessment of the vasomotor responses by intracoronary acetylcholine and assessment of coronary microvascular dysfunction (CMD) by measuring the coronary flow reserve (CFR). VSA and MVA were diagnosed on the basis of the criteria as proposed by the Coronary Vasomotor Disorders International Study Group (COVADIS). The predictive risk factors were analyzed by means of logistic regression. Results A total of 134 patients were included, median age was 57 years and 85.1% were female. The Ach-test revealed VSA in 95 patients (70.9%), MVA in 13 patients (9.7%) and a negative Ach-test in 26 patients (19.4%). A multivariable logistic regression model showed smoking as an independent variable for a positive Ach-test (OR of 3.0 with 95% CI 1.1–8.2; p=0.031) and as an independent predictor for VSA (OR of 2.9 95% CI 1.1–7.9 p=0.039). In addition we showed that migraine (OR of 6.7 95% CI 1.4–32.9 p=0.019) is an independent predictor for MVA and MVA has a strong association with female patients who have a history of recurrent miscarriages (p=0.015). Conclusion MVA and VSA are associated with different risk factors which support a different underlying pathophysiology. Smoking is an independent predictor for a positive Ach-test and an independent predictor for VSA. In addition, we showed that migraine is an independent predictor for MVA and MVA has a strong association with female patients who have a history of miscarriages. MVA and VSA require a different treatment strategy and because there are no clear predictive values for a positive Ach-test, it is important to support identification with an Ach-test. Funding Acknowledgement Type of funding source: None

Mental Health Status in Patients Undergoing Intracoronary Acetylcholine Provocation Test.

Previous studies showed the relation of mental distress such as anxiety and depression to coronary vasoconstriction and myocardial ischemia. However, the mental health status of patients suspected to have vasospastic angina is unclear. A total of 99 patients underwent intracoronary acetylcholine (ACh) provocation tests for the diagnosis of vasospastic angina and mental health assessment using the 12-item General Health Questionnaire (GHQ-12) and State-Trait Anxiety Inventory Form Y (STAI Y-2). Patients with binary GHQ-12 ≥ 4 were defined as having poor mental health. Median GHQ-12 and STAI Y-2 were 3 [1, 6] and 44 [36, 50]. Forty-one (41%) patients had binary GHQ-12 ≥ 4, and 48 (48%) had positive ACh provocation tests. The number of provoked vasospasms and rate of electrocardiographic change and chest pain during ACh tests were not significantly different between patients with and without GHQ-12 ≥ 4. The incidence of positive ACh provocation test was similar between the two groups (49% vs. 48%, p = 1.00). The multivariable analysis indicated that younger age, no history of percutaneous coronary intervention and no diabetes mellitus were factors associated with higher GHQ-12 and/or STAI Y-2 scores. More than 40% of patients who underwent ACh provocation tests had poor mental condition. No impact of mental distress on positive ACh tests was found in this study.

Decreased resting coronary flow and impaired endothelial function in patients with vasospastic angina.

Coronary endothelial and circulatory dysfunction plays important roles in the pathogenesis of vasospastic angina (VSA). However, a complete understanding of the entire coronary circulation including microvasculature in patients with VSA is lacking. A total of 32 patients without obstructive coronary artery disease in the left descending coronary artery, who underwent an intracoronary acetylcholine (ACh) provocation test for diagnosis of VSA, were enrolled prospectively. A positive diagnosis of the ACh test was defined as total/subtotal coronary artery narrowing accompanied by chest pain and/or ischemic ECG changes. Angina frequency and severity at baseline, and 1 and 3 months were recorded. Coronary circulation was evaluated invasively using a thermodilution method by obtaining the mean transit time (Tmn) at rest and hyperemia, coronary flow reserve, and index of microcirculatory resistance. Systemic endothelial function was assessed by the reactive hyperemia index. There were 14 (44%) and 18 (56%) patients with and without a positive ACh provocation test. The baseline characteristics did not differ significantly between the two groups. Patients with VSA had a significantly lower reactive hyperemia index compared with those without VSA (1.70±0.33 vs. 2.12±0.53, P=0.02). Coronary flow reserve, index of microcirculatory resistance, and hyperemic Tmn were not different between the two groups, whereas resting Tmn was significantly longer in patients with VSA (1.20±0.44 vs. 0.71±0.37, P=0.002). Although the frequency and severity of angina improved from baseline to 1 and 3 months in patients with both positive and negative ACh tests, there was no difference between the two groups. Patients with VSA had decreased resting coronary flow and impaired endothelial function.

Safety and usefulness of acetylcholine provocation test in patients with no culprit lesions on emergency coronary angiography

BackgroundVasospastic angina (VSA), which often causes acute coronary syndrome (ACS), can be diagnosed by intracoronary acetylcholine (ACh) provocation test. However, the safety and usefulness of ACh provocation test in ACS patients on emergency coronary angiography (CAG) compared to non-emergency settings are unclear. MethodsA total of 529 patients undergoing ACh provocation test during emergency or non-emergency CAG were included. Patients with resuscitated cardiac arrest were excluded. The primary endpoint was adverse events defined as a composite of death, ventricular fibrillation or sustained ventricular tachycardia, myocardial infarction, cardiogenic shock, cardiac tamponade, and stroke within 24 h after ACh provocation test. ResultsThere were no significant differences of the clinical characteristics between the groups of emergency (n = 84) and non-emergency (n = 445) ACh provocation test. The rate of positive ACh provocation test was similar between the 2 groups (50% vs. 49%, p = 0.81). Similarly, the incidence of adverse events in patients with emergency and non-emergency ACh provocation test did not significantly differ (1.2% vs. 1.3%, p = 1.00). ConclusionACh provocation test can be safely performed in ACS patients with no obstructive culprit lesions on emergency CAG, and may be useful to diagnose VSA in those patients.

Feasibility and safety of outpatient cardiac catheterization with intracoronary acetylcholine provocation test.

Intracoronary acetylcholine (ACh) provocation test is useful to diagnose vasospastic angina. Although outpatient coronary angiography has been widely performed in current clinical settings, the feasibility and safety of ACh provocation test in outpatient services are unclear. A total of 323 patients, who electively underwent ACh provocation test in hospitalization and outpatient services, were included. Coronary angiography was performed after insertion of a temporary pacing electrode in the right ventricle. The positive diagnosis of intracoronary ACh provocation test was defined as total or subtotal coronary artery narrowing accompanied by chest pain and/or ischemic electrocardiographic changes. Cardiac complications defined as composite of death, ventricular fibrillation or sustained ventricular tachycardia, myocardial infarction, cardiogenic shock, and cardiac tamponade, were evaluated. There were 201 patients (62%) in the hospitalization group and 122 patients (38%) in the outpatient group. The incidence of positive ACh provocation test was similar between the 2 groups (47 vs. 54%, p=0.21). Coronary angiography in the outpatient group was performed through the radial artery, mostly (98%) with a 4F sheath. Venous access site was not significantly different between the 2 groups, and the sheath size was 5F in all cases. There were 2 cases (1.0%) of cardiac complications in the hospitalization group, whereas 1 case (0.8%), which led to unexpected hospitalization, occurred in the outpatient group. In conclusion, intracoronary ACh provocation test for the diagnosis of vasospastic angina in outpatient services was feasible and safe in selected patients.

Sex-Related Differences in Vasomotor Function in Patients With Angina and Unobstructed Coronary Arteries

BackgroundCoronary vasomotor dysfunction is an important mechanism for angina in patients with unobstructed coronary arteries. ObjectivesThe purpose of this study was to determine sex differences in the prevalence and clinical presentation of vasomotor dysfunction in a European population and to examine sex differences in the dose of acetylcholine leading to a positive acetylcholine provocation test (ACH test). MethodsBetween 2007 and 2014, we included 1,379 consecutive patients with stable angina, unobstructed coronaries and ACH test performed for epicardial vasospasm or coronary microvascular dysfunction (CMD) due to microvascular spasm. The predictive value of sex, risk factors, symptoms, and noninvasive test results was analyzed by means of logistic regression. ResultsThe mean patient age was 62 years, and 42% were male. There were 813 patients (59%) with a pathological ACH test, 33% for CMD and 26% for epicardial vasospasm. A pathological test was more common in females (70% vs. 43%; p < 0.001). In a multivariable logistic regression model the sex difference was statistically significant with a female–male odds ratio for CMD and epicardial vasospasm of 4.2 (95% confidence interval: 3.1 to 5.5; p < 0.001) and 2.3 (95% confidence interval: 1.7 to 3.1; p < 0.001), respectively. Effort-related symptoms, but neither risk factors nor noninvasive stress tests, contributed to predicting a pathological test. Female patients were more sensitive to acetylcholine with vasomotor dysfunction occurring at lower ACH doses compared with male patients. ConclusionsVasomotor dysfunction is frequent in patients with angina and unobstructed coronaries in a European population. Female patients have a higher prevalence of vasomotor dysfunction (especially CMD) compared with male patients. A pathological ACH test was observed at lower ACH doses in women compared with men.

Relation between severity of myocardial bridge and vasospasm

BackgroundMyocardial bridge (MB) has been reported to induce cardiac complications including coronary vasospasm. Although MB has some anatomical and morphological variations, the association of these variations with vasospasm is unclear. The aim of this study was to investigate the relation between morphological severity of MB and vasospasm induced by acetylcholine (ACh) provocation test. MethodsA total of 392 patients without coronary stent in the left anterior descending artery (LAD) undergoing intracoronary ACh provocation test were included. Angiographic coronary artery vasospasm was defined as total or subtotal occlusion induced by ACh provocation. MB was identified on coronary angiography as a milking effect. Total bridged length and maximum percent systolic compression of MB in the LAD were analyzed quantitatively. ResultsMBs in the LAD were identified in 140 patients (36%), mostly in the mid segment. Patients with MB in the LAD had greater number of provoked vasospasm in the LAD and positive ACh provocation test compared to those without. The bridged length positively correlated with percent systolic compression of MB (r=0.37, p<0.001). In the receiver operating characteristic curve analysis, both bridged length and percent systolic compression of MB significantly predicted the provoked LAD spasm (AUC 0.74, p<0.001, and AUC 0.68, p<0.001). Multivariate regression analysis demonstrated these factors as independent predictors for provoked LAD spasm. ConclusionMB, especially morphologically severe MB, may induce greater coronary vasospasm.

Predictive value of coronary artery dilation response to nitrate for a positive intracoronary acetylcholine provocation test

Baseline coronary artery diameter and coronary artery dilation response to nitrate are associated with coronary vasoreactivity. The present study investigated the predictive value of coronary artery tone for a positive intracoronary acetylcholine (ACh) provocation test. A total of 197 patients who underwent an ACh provocation test in the right coronary artery were included. A positive ACh provocation test was defined as transient total or subtotal occlusion of a coronary artery with signs/symptoms of myocardial ischemia. The segment, from the ostium to the bifurcation, of the right coronary artery was analyzed quantitatively. Coronary artery dilation response to isosorbide dinitrate (ISDN) was defined as the mean lumen diameter after an intracoronary injection of ISDN divided by the diameter before administration of ACh (i.e. baseline coronary artery diameter). After the administration of ACh, 49 patients (24.9%) had a positive ACh provocation test. Smaller baseline right coronary artery diameter (2.35±0.45 vs. 2.73±0.48 mm, P<0.001) and greater right coronary artery dilation response to ISDN (1.34±0.12 vs. 1.15±0.11, P<0.001) were observed in patients with a positive ACh provocation test. The receiver operating characteristic curve for baseline coronary artery diameter poorly predicted the occurrence of a positive ACh provocation test (area under the curve 0.71). The predictive values of dilation response of the right coronary artery to ISDN for the occurrence of a positive ACh provocation test (area under the curve 0.87) was significantly better compared with that of baseline right coronary artery diameter (P<0.001). Coronary artery dilation response to nitrate is a more accurate predictor of a positive intracoronary ACh provocation test compared with baseline coronary artery diameter.

Clinical Determinants of a Positive Acetylcholine Provocation Test in an Australian Setting

Clinical Determinants of a Positive Acetylcholine Provocation Test in an Australian Setting

Left ventricular dysfunction due to diffuse multiple vessel coronary artery spasm can be concealed in dilated cardiomyopathy

Many patients with idiopathic dilated cardiomyopathy (DCM) have been diagnosed on the basis of the exclusion of significant coronary stenosis and the presence of left ventricular (LV) dysfunction. In the present study, we investigated the possibility that coronary multispasm is one of the mechanisms leading to diffuse idiopathic DCM-like LV dysfunction. Forty-two patients with severely depressed LV function but without significant coronary stenosis were enrolled (baseline LV ejection fraction, 33 ± 11%). An acetylcholine (ACh) provocation test was performed at the time of coronary angiography. In patients with a positive ACh provocation test (n = 20), coronary angiography revealed multivessel diffuse coronary spasm with marked electrocardiogram changes. In patients with a negative ACh provocation test (n = 22), significant findings compatible with idiopathic DCM were more frequently observed on magnetic resonance imaging (MRI) or in LV biopsies compared with the ACh-positive group (MRI, 73% vs. 12%; and LV biopsy, 71% vs. 0%, respectively; P < 0.01). In the ACh-positive group, LV function significantly improved after the administration of calcium channel blockers (LV ejection fraction, 34 ± 12% vs. 54 ± 10%; and brain natriuretic peptide, 803 ± 482 pg/mL vs. 69 ± 84 pg/mL, at baseline and 1 year, respectively; P < 0.01). Our results raise the possibility that patients with LV dysfunction due to repeated coronary multispasm are being diagnosed as idiopathic DCM, and that calcium channel blockers may prove to be a promising therapeutic strategy in those patients.

Effect of Long-Term Nitrate Treatment on Cardiac Events in Patients With Vasospastic Angina

Nitrates have been widely used as anti-ischemic drugs in patients with vasospastic angina (VSA). However, the effect of long-term nitrate treatment on cardiac events in VSA patients remains unclear. Two-hundred and thirty-one patients with VSA who had not been receiving any antiischemic drugs, including calcium channel blockers (CCBs), nitrates, nicorandil, or any combination of these medications were prospectively enrolled in the present study. All patients had a positive acetylcholine provocation test with normal coronary angiograms, and they received CCBs after enrollment. They were divided into 2 groups based on whether nitrates were included in the treatment: a nitrate group (n=86) and a without nitrate group (n=145). The baseline clinical characteristics and frequency of anginal attacks within 48h before enrollment were similar between the 2 groups. With a median follow-up period of 70.5 months, 29 patients developed cardiac events, including 7 sudden cardiac deaths and 22 re-admissions for acute coronary syndrome. Cardiac events occurred in 19.8% of the nitrate group and in only 8.3% of the patients who were not taking nitrates (P=0.015). In a multivariate analysis, long-term nitrate treatment (hazard ratio 5.18, 95% confidence interval: 1.69-15.89, P=0.004) was an independent predictor of cardiac events. These data indicate that long-term nitrate treatment in addition to CCBs might not reduce cardiac events in VSA patients.