Intracoronary Acetylcholine Testing Research Articles

Assessment of TIMI frame count pre- and post- intracoronary acetylcholine administration in patients with angina and non-obstructive coronary arteries (ANOCA)

Abstract Background Patients with Angina and unobstructed coronary arteries (ANOCA) represent a diagnostic challenge. Current ESC guidelines on the management of patients with chronic coronary syndrome recommend intracoronary spasm testing and coronary spasm represents a frequent diagnosis in such patients. Previous studies have shown that coronary artery flow assessments during acetylcholine testing frequently show non-uniform results. Purpose The aim of the present study was to assess changes in TIMI Frame Count (a quantitative method for the assessment of coronary artery flow) pre- and post- intracoronary acetylcholine testing in patients with ANOCA. Methods From 2007 to 2018, a total of 141 consecutive patients (51.8% female, mean age 61 ± 13.2 years) were included in the study. Among them, 63 patients (45%) presented with myocardial infarction with unobstructed coronary arteries, while 78 patients (55%) presented with stable angina and unobstructed coronaries. Following diagnostic angiography, all patients underwent intracoronary acetylcholine testing using a standardized protocol. TIMI frame count (TFC) was measured both for LAD and LCX before and after ACh injection, and post nitroglycerine injection. All counted frames were adjusted to a frame rate of 30 frames per second (fps). Furthermore, TFC of the LAD was divided by 1.7 to obtain the corrected TFC (cTFC). Results Of all 141 patients, coronary spasm was found in 98 patients (70%) during ACh testing (44% epicardial and 56% microvascular spasm). In the spasm cohort, the median cTFC in the LAD pre-ACh was 21.8 fps (quartiles: 16.3 – 30.0), decreased to 12.9 fps (8.8 - 19.2) post-ACh, and increased to 15.9 fps (10.6 - 21.3) post-nitro. The difference in the LAD between pre-ACh and post-ACh was statistically significant (p < 0.001). In the LCX the median TFC was 26.5 fps (15.0 – 40.5) pre-ACh, decreased to 16.0 fps (11.5 - 28.5) post-ACh and reached 24.0 fps (15.5 - 33.3) post-nitro. Again, this reduction from pre-ACh to post-ACh was statistically significant (p < 0.001). In the negative spasm cohort median cTFC for the LAD was 22.9 fps (16.0 – 18.2) pre-Ach, 15.3 fps (9.4 – 24.7) post-ACh and 15.8 fps (10.6 - 24.7) post-nitro, TFC for LCX was 24.0 fps (18.0 - 36.0) pre-ACh, 18.0 fps (12.0 – 33.0) post-ACh and 24.0 fps (12.0 – 34.0) post-nitro. The change in cTFC/TFC pre-ACh compared to post-ACh was statistically significant for both coronary arteries (LAD, p=0.012; LCX p=0.005, Table 1). Interestingly, in the spasm cohort 22% of LAD and 32% of LCX vessels showed higher TFC post-ACh compared to pre-ACh (Figure 1). Conclusions In patients with ANOCA and coronary spasm assessment of TIMI frame count reveals a hetereogeneous response. The majority of cases shows a decrease in TFC suggesting an increase in flow despite coronary spasm. This interesting finding allows speculations about the presence of coronary shunts.Figure 1

Diagnostic potential of relative changes in high-sensitivity troponin levels during intracoronary acetylcholine provocation testing

Abstract Background Intracoronary acetylcholine (ACh) provocation testing is useful for the diagnosis of vasospastic angina (VSA). However, the positive or negative diagnosis of ACh testing is often challenging when lacking typical anginal symptoms and electrocardiographic changes during provocation tests. We hypothesized that relative changes in cardiac troponin levels during ACh provocation testing may be suggestive of myocardial ischemia and would be helpful for the VSA diagnosis. Purpose To evaluate the diagnostic potential of relative changes in high sensitivity troponin I (hs-TnI) levels during intracoronary ACh provocation test. Methods This preliminary study included a total of 29 patients undergoing invasive coronary angiography with or without ACh provocation tests. Patients were divided into three groups; no ACh provocation tests (i.e. angiography alone), negative ACh tests, and positive ACh tests. Blood samples were obtained twice, before and after angiography, through the arterial sheath to evaluate hs-TnI. The primary measure was relative changes in hs-TnI (i.e. Δhs-TnI). Positive ACh provocation test was defined as total or subtotal coronary occlusion accompanied by chest pain and/or ischemic electrocardiographic changes. Results Of the 29 patients, 10 (34.5%) underwent coronary angiography alone, while ACh provocation testing was performed in 19 (65.5%) patients, of whom 7 (36.8%) and 12 (63.2%) had negative and positive ACh test results. Overall, the mean time interval between the blood sample collections was 76 minutes. Levels of hs-TnI before angiography did not differ significantly in the no, negative, and positive ACh test groups (5.3 [2.8, 8.6] vs. 2.9 [1.3, 8.8] vs. 3.3 [1.6, 8.5] pg/ml, p=0.76), while Δhs-TnI was highest in the positive ACh test group, followed by the negative and no ACh test groups (4.2 [0.5, 8.1] vs. 0.8 [0.4, 4.6] vs. −0.3 [−0.6, 0.3], p=0.002) (Figure). Conclusions In patients undergoing intracoronary ACh testing for the VSA diagnosis, a relative increase in Δhs-TnI during angiography was observed than in those who did not undergo the provocation tests, particularly when the ACh test diagnosis was positive. Our findings suggest that Δhs-TnI has the potential to aid in the positive or negative diagnosis of ACh provocation testing.

Safety and Usefulness of Intracoronary Acetylcholine 200 μg Into the Left Coronary Artery as Vasoreactivity Testing: Comparisons With Intracoronary Acetylcholine Maximum 100 μg.

We retrospectively analyzed the usefulness and safety of intracoronary acetylcholine (ACh) 200 μg into the left coronary artery (LCA) as vasoreactivity testing compared with intracoronary ACh 100 μg. We recruited 1433 patients who had angina-like chest pain and intracoronary ACh testing in the LCA, including 1234 patients with a maximum ACh 100 μg and 199 patients with a maximum ACh 200 μg. ACh was injected in incremental doses of 20/50/100/200 μg into the LCA. Positive spasm was defined as ≥ 90% stenosis, usual chest pain, and ischemic electrocardiogram (ECG) changes. The incidence of coronary constriction ≥ 90%, usual chest pain, and ischemic ECG changes with a maximum ACh of 100 μg was markedly higher than that with a maximum ACh of 200 μg. The frequency of unusual chest pain in patients with a maximum ACh of 200 μg was higher than that in those with a maximum ACh of 100 μg (13% vs. 3%, p < 0.001). In patients with rest angina, positive spasm of maximum ACh 100 μg was significantly higher than that of maximum ACh 200 μg, whereas there was no difference regarding positive spasm in patients with atypical chest pain between the two ACh doses. Major complications (1.38% vs. 1.51%, p = 0.8565) and the occurrence of paroxysmal atrial fibrillation (1.81% vs. 2.63%, p = 0.6307) during ACh testing in the LCA were not different between the two maximum ACH doses. Intracoronary ACh 200 μg into the LCA is clinically useful and safe for vasoreactivity testing when intracoronary ACh 100 μg dose not provoke spasms.

The Need for Separate Testing with Acetylcholine for the Assessment of Endothelial Dysfunction and Coronary Artery Spasm.

Intracoronary acetylcholine (ACH) testing is clinically useful to diagnose the presence of the coronary vasomotor disorders coronary endothelial dysfunction and coronary epicardial/microvascular spasm. In Western countries, continuous intracoronary injection of ACH for 2-3 minutes without a pacemaker is the usual method, while rapid injection of ACH for 20-30 seconds with a pacemaker is the traditional procedure in Japan. Coronary microvascular spasm is often observed in Western populations, whereas coronary epicardial spasm is frequently seen in Japanese subjects. Methodological differences between Western and Japanese protocols may lead to the opposite prevalence of coronary vasomotor disorders. This article discusses the optimal method for diagnosing endothelial dysfunction and epicardial/microvascular spasm based on previous reports, and compares intracoronary ACH testing performed by Western cardiologists with that by Japanese physicians.

Importance of provoked spasms at the sites of nonobstructive stenosis as well as at the sites of obstructive stenosis in patients with obstructive coronary arteries and coronary spasm.

There are few reports regarding the prognosis in patients with obstructive coronary artery disease (OCAD) and vasospastic angina (VSA). This study investigated the clinical characteristics and clinical outcomes in patients with VSA and OCAD, especially regarding provoked spasm phenotypes and sites. This was a retrospective, observational, single-center study of 403 patients with typical or atypical angina-like chest pain undergoing acetylcholine (ACH) spasm provocation testing and OCAD. An obstructed coronary artery was defined as ≥50% luminal narrowing. We defined positive epicardial spasm as ≥90% transient stenosis and usual chest symptoms or ischemic ECG changes. Among these 403 patients with OCAD, positive spasm by intracoronary ACH testing was observed in 196 patients (49%), whereas negative spasm was found in the remaining 207 patients (51%). The clinical outcomes in the patients with OCAD and provoked spasm were not different according to the provoked-spasm phenotypes. Furthermore, the clinical outcomes were unsatisfactory in the patients with spasm at the site of nonobstructive lesion alone compared with those with spasm at the site of obstructive and nonobstructive lesions. We should precisely diagnose patients with OCAD who have provoked spasm by using intracoronary ACH testing and medicate the nonobstructive vessels in patients with OCAD and VSA under optimal coronary vasodilators.

Comparison of Baseline and Post-Nitrate Exercise Testing in Patients with Angina but Non-Obstructed Coronary Arteries with Different Acetylcholine Test Results.

Background: Intracoronary acetylcholine testing may induce epicardial coronary artery spasm (CAS) or coronary microvascular spasm (CMVS) in patients with angina syndromes but non-obstructive coronary artery disease, but their causal role in individual patients is not always clear. In this prospective, observational single-center study, we aimed to assess whether (1) the induction of myocardial ischemia/angina by electrocardiogram (ECG) exercise stress test (EST) differs between patients showing different results in response to acetylcholine testing (i.e., CAS, CMVS, or no spasm); (2) the preventive administration of short-acting nitrates has any different effects on the EST of those patients who showed a positive basal EST. We expected that if exercise-induced angina and/or ischemic ECG changes are related to CAS, they should improve after nitrates administration, whereas they should not significantly improve if they are caused by CMVS. Methods: We enrolled 81 patients with angina syndromes and non-obstructive coronary artery disease, who were divided into three groups according to acetylcholine testing: 40 patients with CAS (CAS-group), 14 with CMVS (CMVS-groups), and 27 with a negative test (NEG-group). All patients underwent a basal EST (B-EST). Patients with a positive B-EST repeated the test 24-48 h later, 5 min after the administration of short-acting nitrates (N-EST). Results: There were no significant differences among the groups in terms of the B-EST results. B-EST was positive in eight (20%) patients in the CAS-group, seven (50%) in the CMVS-group, and six (22%) in the NEG-group (p = 0.076). N-EST, performed in eight, six, and five of these patients, also showed similar results in the three groups. Furthermore, the N-EST results also did not significantly differ compared to B-EST in any group, remaining positive in seven (87.5%), four (66.7%), and four (80%) patients in the CAS-group, CMVS-group, and NEG-group, respectively (p = 0.78). Conclusions: Our data show that patients with angina and non-obstructive coronary artery disease show largely comparable results of the ECG exercise stress test and similar poor effects of short-acting nitrates on abnormal ECG exercise stress test results. On the whole, our findings suggest caution in attributing to the results of Ach testing a definite causal role for the clinical syndrome in individual patients.

Coronary tortuosity in patients with acetylcholine-induced coronary microvascular spasm

Abstract Background Angina pectoris in the absence of relevant epicardial stenoses (ANOCA) is frequently caused by coronary microvascular spasm. It has been speculated that the morphology of epicardial coronary arteries is associated with microvascular spasm. One hypothesis is that the vasoconstriction of microvessels leads to intraluminal pressure increase in the vascular segments proximal to the spasm, which may shift the balance of vessel forces toward vessel elongation resulting in coronary tortuosity. Purpose We assessed the relationship between epicardial coronary tortuosity and coronary spasm to elucidate a potential relationship between structural and functional coronary abnormalities. Methods 610 patients (39% male, mean age 61 years) with stable angina yet unobstructed coronary arteries (&amp;lt;50% stenosis) were included in this study. All patients underwent invasive diagnostic coronary angiography followed by intracoronary acetylcholine (ACh) testing according to a standardized protocol. The ACh test was considered “positive” in the presence of (a) angina, ischemic ECG shifts during the test and ≥90% coronary diameter reduction (“epicardial spasm”) or (b) all above without epicardial spasm (“microvascular spasm”). Assessment of coronary tortuosity was performed using left and right coronary images in multiple projections in a blinded fashion. The number and angles of the coronary curves in late diastole determined the severity of coronary tortuosity previously defined by Eleid. Patients were divided into those with at least moderate tortuosity versus those with no or mild tortuosity. Results ACh-testing revealed epicardial spasm in 179 (29%) and microvascular spasm in 172 (28%) patients. The ACh-test was negative/inconclusive in the remaining 259 patients (43%). There were 298 patients (49%) with at least moderate coronary tortuosity. The remaining 312 patients had no or mild coronary tortuosity (51%). Patients with at least moderate tortuosity were more likely to have microvascular spasm (99 patients of 172 with microvascular spasm had at least moderate coronary tortuosity (58%) vs. 76 patients of 179 with epicardial spasm (43%) vs. 126 patients of 259 with negative/inconclusive ACh test (49%), p=0.017). Analysis of coronary tortuosity in patients with positive ACh-test showed that patients with at least moderate coronary tortuosity (n=175) had significantly more microvascular spasm (57%) than epicardial spasm (43%) (p=0.005). We also found that at least moderate coronary tortuosity was significantly more often found in patients with hypertension compared to patients without hypertension (230/438 vs. 71/172, p=0.015). Conclusions In this large cohort of ANOCA patients coronary tortuosity was associated with hypertension and microvascular spasm. Our results provide interesting insights into the relationship of coronary morphology and vasomotor function. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Berthold-Leibinger-Foundation, Ditzingen, Germany

Clinical Outcomes and Provoked Epicardial Spasm Phenotypes via Intracoronary Acetylcholine Testing in 680 Patients with Angina and Nonobstructive Coronary Arteries.

Background: Epicardial spasm (ES) phenotypes may be related to the prognosis in patients with coronary spastic angina. Objectives: The purpose of this study was to elucidate the relationship between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection and prognosis in patients with angina and nonobstructive coronary artery disease (ANOCAD). Methods: This was a retrospective, observational, single-center study of 680 patients with ANOCAD. ACh spasm provocation tests on both coronary arteries were performed without administering nitroglycerine to relieve provoked spasm in a first-attempt artery. ACh was injected in incremental doses of 20/50/100/200 μg into the left coronary artery and 20/50/80 μg into the right coronary artery. Positive ES was defined as ≥90% stenosis and usual chest pain and ischemic ECG changes. Results: Provoked positive ES was observed in 310 patients (46%), including 85 patients (13%) with focal spasm, 150 patients (22%) with diffuse spasm, and 75 patients (11%) with combined spasm (diffuse spasm and focal spasm), whereas the remaining 370 patients (54%) had no provoked spasm. An unclassified ACh test was observed in 186 patients (27%), while 184 patients (27%) had a complete negative ACh test. The clinical outcomes in patients with complete negative ES were satisfactory compared with those with positive ES and unclassified ACh test results. The prognosis in patients with an unclassified ACh test was not different from those with a positive ES. Furthermore, prognosis in patients with ES phenotypes was not different among the three groups. Conclusions: There was no correlation between provoked ES phenotypes via intracoronary ACh testing and prognosis in patients with ANOCAD; however, clinical outcomes in patients with positive ES and unclassified ACh tests were worse compared to those with complete negative ACh tests. We should focus on the treatments in patients with unclassified ACh tests as well as those with ESs.

Clinical features and outcomes of patients with stable or unstable chest pain and no-obstructive coronary artery disease

BackgroundCoronary microvascular dysfunction can be responsible for both stable angina and acute coronary syndrome (ACS). There are scarce data, however, about comparisons of clinical characteristics and outcomes of these 2 groups of patients.Materials and methodsWe studied 47 consecutive patients who underwent coronary angiography for angina syndromes and showed no obstructive stenosis. Patients were divided in 2 groups, according to their clinical presentation, i.e., stable angina (n = 21) or non-ST segment elevation ACS (NSTE-ACS; n = 26). An intracoronary acetylcholine (Ach) test was performed in 12 and 17 patients of the 2 groups, respectively. Angina status, assessed by Seattle Angina Questionnaire (SAQ), and clinical events were assessed after 1, 6, and 30 months. An exercise stress test was performed 1 month after discharge.ResultsClinical characteristics and exercise test results of the 2 groups were largely similar. Ach testing induced epicardial or microvascular spasm in 6 (50.0%) and 10 (58.8%) stable and NSTE-ACS patients, respectively (p = 0.72). Stable patients reported higher rates of angina, compared to NSTE-ACS patients, both at 1 (p = 0.04) and 30 months (81 vs. 50%, p = 0.036) of follow-up. SAQ scores were also lower in stable vs. NSTE-ACS patients. Ach testing results showed no association with clinical outcomes.ConclusionClinical characteristics and exercise and Ach testing results are similar in angina patients with no-obstructive coronary artery disease with a stable or NSTE-ACS presentation. Stable patients show a worse symptomatic outcome irrespective of Ach test results.

Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis

BackgroundCoronary spasm has been suggested to be the underlying mechanism of chest pain in patients with myocarditis and unobstructed coronary arteries. Here we sought to investigate a potential association between virus type and coronary spasm endotype in patients with biopsy-proven viral myocarditis. MethodsA total of 618 consecutive patients with unobstructed coronary arteries who underwent endomyocardial biopsy between 2008 and 2018 were screened. Viral myocarditis defined as (immuno-)histological evidence of myocardial inflammation and proof of viral genome by PCR was confirmed in 114 patients. Of these, 34 patients had undergone additional intracoronary acetylcholine (ACh) testing and served as the final study cohort. ResultsPatients in this study were 51 ± 27 years old, 41% were female and mean left ventricular ejection fraction was 58 ± 23%. Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%). ACh testing revealed epicardial spasm in 10 patients (29%) and microvascular spasm in 11 patients (32%). The rate of coronary spasm was higher in patients with PVB19-associated myocarditis compared to those with HHV6-associated myocarditis (80% vs. 33%, p = 0.031). In particular, there was a higher prevalence of microvascular spasm in patients with PVB19 compared to HHV6 infection (45% vs. 0%, p = 0.018). ConclusionCoronary spasm is a frequent finding in patients with biopsy-proven viral myocarditis supporting the hypothesis that coronary spasm may contribute to chest pain in these patients. We observed a particular association of microvascular spasm with PVB19 infection.

The Heterogeneity of Intracoronary Acetylcholine Testing Results Showing Positivity for Either the Right or Left Coronary Artery

The Heterogeneity of Intracoronary Acetylcholine Testing Results Showing Positivity for Either the Right or Left Coronary Artery

Coronary artery spasm and impaired myocardial perfusion in patients with ANOCA: Predictors from a multimodality study using stress CMR and acetylcholine testing

BackgroundFunctional coronary disorders such as coronary spasm and microvascular dysfunction (including microvascular spasm and impaired microvascular dilatation) are frequent findings among patients with angina and non-obstructed coronary arteries (ANOCA). In this study, we investigated a potential association of coronary spasm and myocardial perfusion abnormalities as well as predictors of such functional coronary disorders in ANOCA patients using a multimodality diagnostic strategy including adenosine stress CMR and intracoronary acetylcholine testing. MethodsWe enrolled 129 patients with ANOCA who underwent acetylcholine testing and adenosine stress perfusion CMR. Patients were allocated to 3 groups according to their spasm testing result with regard to standardized COVADIS criteria: 1) epicardial spasm, 2) microvascular spasm, and 3) no spasm. The myocardial perfusion reserve index (MPRI) was semiquantitatively determined from adenosine stress perfusion CMR. Multivariate regression analyses were performed to identify predictors of coronary functional disorders. ResultsPatients with epicardial spasm had lower MPRI than patients without, whereas MPRI was preserved in patients with microvascular spasm. Multivariate analyses revealed age, previous myocardial infarction, LVEF and epicardial spasm as independent predictors of diminished MPRI, whereas previous PCI was associated with epicardial spasm, and female sex was a strong predictor of microvascular spasm. ConclusionsOur results demonstrate coexistence of different functional coronary disorder endotypes involving the macro- and microvascular level of the coronary circulation in patients with ANOCA. We demonstrate that epicardial spasm is associated with diminished myocardial perfusion reserve and report further predictors of coronary functional disorders.

Intracoronary acetylcholine testing among 746 consecutive Japanese patients with angina-like chest pain and unobstructed coronary artery disease.

Aims Intracoronary acetylcholine (ACh) testing is useful for the detection of epicardial spasm (ES) and coronary microvascular spasm (CMS). We retrospectively analysed the incidence of ES and CMS in consecutive Japanese patients with unobstructed coronary artery disease.Methods and resultsFrom January 1991 to February 2019, we performed intracoronary ACh testing of 1864 patients. Among these patients, a total of 746 consecutive patients (254 women, mean age 64 ± 11 years) who underwent first diagnostic angiography for suspected myocardial ischaemia and had unobstructed coronary arteries (<50%) were enrolled. Epicardial spasm was defined as ≥90% stenosis and usual chest symptoms and ischaemic ECG changes, while CMS was defined as <75% stenosis and usual chest symptoms and ischaemic ECG changes. We performed intracoronary ACh testing on both coronary arteries in 96% (716/746) of all subjects. Overall, ES was found in 329 patients (44%), whereas CMS was revealed in 40 patients (5%) including 4 patients with coexisting ES. In patients with ES, women made up 22%, and approximately three-quarters of the patients had resting chest pain. In contrast, women composed 65% (26/40) of those with CMS, and 15 patients with CMS had another chest symptom. Coronary microvascular spasm was frequently observed in the left coronary artery (LCA) but not the right coronary artery. Electrical cardioversion was necessary for two patients.Conclusions Coronary microvascular spasm was recognized in only 5% of consecutive Japanese patients with unobstructed coronary artery disease, whereas ES was revealed in 44% of those patients. Coronary microvascular spasm was often observed in women and in the LCA.

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 20/50/100μg into the left coronary artery and 20/50/80μg 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.

Intracoronary acetylcholine spasm testing: differences in epicardial coronary artery response between smooth and atherosclerotic coronary arteries

Abstract Background Coronary artery spasm is an established cause for angina pectoris. Epicardial coronary spasm may occur in patients with obstructed as well as unobstructed coronary arteries. Previous studies have suggested that epicardial plaque/atherosclerosis is a prerequisite for the development of epicardial spasm. The aim of the present study was to compare the results of intracoronary acetylcholine (ACh) testing in patients with signs and symptoms of myocardial ischemia with completely smooth versus atherosclerotic yet unobstructed epicardial arteries. Methods Between 2008 and 2016 a total number of 617 patients with signs and symptoms of myocardial ischemia yet unobstructed epicardial arteries (&amp;lt;50% epicardial stenosis) was included in the present study (mean age 61±11, 61% female). All patients underwent invasive diagnostic coronary angiography followed by intracoronary ACh testing according to a standardized protocol. The ACh-test was considered “positive” in the presence of (a) angina, ischemic ECG shifts during the test and ≥75% focal or diffuse coronary diameter reduction (“epicardial coronary artery spasm”) or (b) ischemic ST-shifts and angina in the absence of epicardial spasm (“microvascular spasm”). All angiograms were assessed regarding any visible epicardial plaque/atherosclerosis in a blinded fashion and patients were categorized into those with completely smooth versus those with atherosclerotic coronary arteries. The analysis included 179 patients (29%) with epicardial spasm and 172 patients with microvascular spasm (28%). The remaining 266 patients (43%) had an uneventful or an inconclusive ACh-test result. Results There were 389 patients (63%) with completely smooth epicardial arteries. The remaining 228 patients (37%) had non-obstructive epicardial plaques &amp;lt;50%. Patients with smooth arteries developed epicardial spasm in 24%, microvascular spasm in 32% and a negative/inconclusive test result in 44% of cases. Patients with atherosclerotic arteries developed epicardial spasm in 38%, microvascular spasm in 21% and an inconclusive/negative test result in 41% of cases. On univariate analysis the presence of epicardial atherosclerosis was associated with epicardial spasm (p=0.006) whereas this was not the case for microvascular spasm (p=0.094). Multivariate analysis revealed the presence of epicardial atherosclerosis (OR 1.921, CI 1.285–2.871, p=0.001) as well as female sex (OR 1.526, CI 1.024–2.274, p=0.038) as independent predictors for epicardial spasm. Conclusion In patients with signs and symptoms of myocardial ischemia yet unobstructed coronary arteries the presence of epicardial atherosclerosis is an independent predictor for the occurrence of epicardial spasm but not microvascular spasm on acetylcholine testing. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Robert-Bosch-Stiftung, Berthold-Leibinger-Stiftung

Age-related differences and vascular function test findings in patients with vasospastic angina

Abstract Background Vasospastic angina (VSA) accounts for the majority of angina cases with no epicardial stenosis and develops amongawide range of age, which is reportedly induced by coronary functional abnormalities including endothelial dysfunction and smooth muscle hypercontraction. However, the relation of noninvasive vascular function tests to VSA remains to be fully elucidated. Purpose The aim of this study was to assess differences in clinical characteristics and findings from noninvasive vascular function tests among groups by age in patients with VSA. Methods We enrolled a total of 732 patients with angina who underwent intracoronary acetylcholine provocation test. VSA was defined as total or subtotal occlusion of epicardial coronary arteries accompanied by chest pain and/or ischemic electrocardiographic changes in response to acetylcholine administration. Patients with VSA were divided into 3 groups by age (young [&amp;lt;50 years], intermediate [50–64 years], and elderly group [≥65 years]). Noninvasive vascular function test findings such as ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), andpercentage of mean arterial pressure (%MAP) were compared among groups by age in patients with VSA. Results Of all patients, 367 (50.1%) were diagnosed as VSA with intracoronary acetylcholine test, including 66 (18.0%), 113 (30.8%), and 188 (51.2%) patients in the young, intermediate, and elderly groups. Among groups by age, there was no significant difference in gender (female, 31.8% vs. 40.7% vs. 44.7%, P=0.19). Patients in the young group were more often smokers and alcohol drinkers than those in the intermediate and elderly groups, while the prevalence of hypertension, dyslipidemia, and diabetes were lower in younger patients. A history of percutaneous coronary intervention was less frequently found in the young group compared tothe intermediate and elderly groups (7.6% vs. 16.8% vs. 20.7%, P=0.033). The baPWV was higher in the elderly group (1424±232 vs. 1537±247 vs. 1774±358 cm/s, P&amp;lt;0.0001), while there was no difference in ABI between the 3 groups. %MAP at arms was significantly and progressively decreased with an increase in age (54.0±4.5% vs. 53.0±2.6% vs. 51.2±2.8%, P&amp;lt;0.0001). Conclusion Our study demonstrated that there were distinct age-related differences in clinical characteristics of patients with VSA. The higher %MAP in younger patients suggests that more impaired endothelial dysfunction may play a role in the development of VSA in this age group. Funding Acknowledgement Type of funding source: None

Mechanisms of angina in patients with biopsy-proven viral myocarditis: insights from intracoronary acetylcholine testing

Abstract Background Patients with myocarditis often present with angina pectoris despite unobstructed coronary arteries. The underlying pathophysiological mechanism of angina in these patients remains to be elucidated. Coronary artery spasm is a well-known cause of angina in patients with unobstructed coronary arteries. In this study, we sought to assess the frequency of coronary vasomotor disorders in patients with biopsy-proven viral myocarditis. Methods In total, 700 consecutive patients who underwent endomyocardial biopsy for suspected myocarditis between 2008 and 2018 were retrospectively screened. Of these patients, viral myocarditis was confirmed in 303 patients defined as histological/immunohistological evidence of myocardial inflammation and presence of viral genome confirmed by PCR. Of these patients, 34 patients had angina despite unobstructed coronary arteries and underwent intracoronary acetylcholine (ACh) provocation testing in search of coronary spasm. Epicardial spasm was defined as acetylcholine-induced reproduction of the patient's symptoms associated with ischemic ECG changes and &amp;gt;90% epicardial vasoconstriction. Microvascular spasm was defined as symptom reproduction and ECG changes in the absence of significant epicardial vasoconstriction. Results Patients were 49±16 years old, 62% were male and left ventricular ejection fraction was 54±16%. Most frequent viruses were parvovirus B19 (PVB19, 59%) and human herpes virus 6 (HHV6, 26%), 2 patients had combined PVB19/HHV6 infection and 3 patients other herpesviruses (CMV, EBV, VZV). Epicardial spasm was observed in 10 patients (29%) during ACh testing and microvascular spasm was found in 11 patients (32%). The rate of coronary spasm (epicardial and microvascular) was higher in the PVB19 subgroup compared to HHV6 (80% vs. 33%, p=0.031). In particular, there was a higher prevalence of microvascular spasm in PVB19 compared to HHV6 (45% vs. 0%, p=0.018). Conclusion We observed a high prevalence of microvascular and epicardial spasm in patients with biopsy-proven viral myocarditis suggesting coronary spasm as a potential underlying mechanism for angina in these patients. Microvascular spasm was most often observed in patients with PVB19-associated myocarditis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Robert-Bosch-Stiftung; Berthold-Leibinger-Stiftung

Sex differences in patients with ischemia and no obstructive coronary disease subjected to intracoronary acetylcholine test in a multicenter registry

Abstract Background Ischemia with no obstructive coronary disease (INOCA) is increasingly diagnosed because of wide performance of coronary angiography. Prevalence of INOCA is higher in women than in men, however the exact pathophysiological mechanisms which may explain this phenomenon are still not very well understood. Objective To evaluate differences in clinical and procedural characteristics between men and women with INOCA subjected to intracoronary acetylcholine test (Ach). Methods A total of 210 women and 148 men with INOCA diagnosed with coronary angiography, were prospectively enrolled in a multicenter, observational registry. Ach test was performed according to clinical indications in all included patients. After 1-year patients were re-evaluated for major cardiovascular events, angina symptoms and prescribed medical treatment. Results Mean age of 60.6±13.6 years old was similar in both populations, but differences were observed in the prevalence of risk factors: active smoking was more frequent among men (43% vs. 17%, p&amp;lt;0.001), who had also a higher number of associated risk factors (≥3 risk factors were present in 31.2% of men vs. 20.2% of women, p&amp;lt;0.01) and more frequent history of percutaneous coronary revascularization (14.2% vs. 6.7%, p=0.03). Women were more prone to have dyspnea than men (35.5% vs. 20.8%, p=0.01). Men had more coronary atherosclerosis in angiography (57.9% vs. 43.7%, p=0.01) and more slow flow in the left anterior descending artery (21.6% vs. 9.0%, p=0.001). Ach was positive in 36.5% of patients, similar in both sexes, with no differences in the type of induced coronary spasm. Among those with a positive Ach test, at one-year, 36% of women vs. 43.6% of men were on optimal medical treatment for vasospasm although the difference was not statistically significant. Importantly, 41.5% of women and 38.1% of men experienced severe symptoms of angina during follow-up. Conclusions Although men with INOCA have a higher risk profile than women and more coronary atherosclerosis, one third of patients present endothelial dysfunction, similar in both groups, indicating that probably other pathophysiological mechanisms are responsible for it in females. Treatment in these patients remains suboptimal and associated with highly impaired quality of life. Funding Acknowledgement Type of funding source: None

Coronary microvascular dysfunction in patients with mild-to-moderate aortic stenosis – Insights from intracoronary acetylcholine testing

Coronary microvascular dysfunction in patients with mild-to-moderate aortic stenosis – Insights from intracoronary acetylcholine testing

Assessment of coronary vasomotor responses to acetylcholine in German and Japanese patients with epicardial coronary spasm-more similarities than differences?

Coronary spasm is an established cause for angina pectoris. Ethnic differences have been suggested among Asian compared to Caucasian patients regarding prevalence, gender distribution, and angiographic patterns of coronary spasm. The aim of this study was to compare contemporary German and Japanese patients with coronary spasm. Between 2011 and 2015, 149 patients with resting angina and unobstructed coronary arteries with acetylcholine-induced epicardial spasm were enrolled in Stuttgart, Germany (n = 69) and Sendai, Japan (n = 80). All patients underwent intracoronary acetylcholine testing according to a standardized protocol. Comprehensive analysis included type of spasm (focal/diffuse), dose of acetylcholine leading to spasm, and frequency of multivessel spasm. Patients in this study were 61 ± 11years old, predominantly female (54%), and had normal left ventricular ejection fraction (73 ± 9%). Diffuse spasm was the most prevalent type of spasm (85%) whereas focal spasm was found in the remaining 15% of patients. 31% of patients had multivessel spasm. Comparing the German with the Japanese patients, distribution of spasm type (focal/diffuse, p = 0.19) and frequency of multivessel spasm (p = 0.22) were comparable. Moreover, when Japanese patients were compared with German patients and diffuse spasm with focal spasm patients, respectively, no significant differences were observed regarding the acetylcholine dose required to induce spasm (p = 0.078 and p = 0.46, respectively). In conclusion, diffuse epicardial coronary spasm is the most frequent finding among German and Japanese patients with resting angina, unobstructed coronary arteries, and epicardial spasm on acetylcholine testing. Japanese and German patients share several similarities including comparable types of spasm and frequency of multivessel spasm.