Acetylcholine Provocation Test Research Articles

Prognostic Impacts of Comorbid Significant Coronary Stenosis and Coronary Artery Spasm in Patients With Stable Coronary Artery Disease.

BACKGROUNDStable coronary artery disease is caused by a variable combination of organic coronary stenosis and functional coronary abnormalities, such as coronary artery spasm. Thus, we examined the clinical importance of comorbid significant coronary stenosis and coronary spasm.METHODS AND RESULTSWe enrolled 236 consecutive patients with suspected angina who underwent acetylcholine provocation testing for coronary spasm and fractional flow reserve (FFR) measurement. Among them, 175 patients were diagnosed as having vasospastic angina (VSA), whereas the remaining 61 had no VSA (non‐VSA group). The patients with VSA were further divided into the following 3 groups based on angiography and FFR: no organic stenosis (≤50% luminal stenosis; VSA‐alone group, n=110), insignificant stenosis of FFR>0.80 (high‐FFR group, n=36), and significant stenosis of FFR≤0.80 (low‐FFR group, n=29). The incidence of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, urgent percutaneous coronary intervention, and hospitalization attributed to unstable angina was evaluated. All patients with VSA received calcium channel blockers, and 28 patients (95%) in the low‐FFR group underwent a planned percutaneous coronary intervention. During a median follow‐up period of 656 days, although the incidence of major adverse cardiovascular events was low and comparable among non‐VSA, VSA‐alone, and high‐FFR groups, the low‐FFR group had an extremely poor prognosis (non‐VSA group, 1.6%; VSA‐alone group, 3.6%; high‐FFR group, 5.6%; low‐FFR group, 27.6%) (P<0.001). Importantly, all 8 patients with major adverse cardiovascular events in the low‐FFR group were appropriately treated with percutaneous coronary intervention and calcium channel blockers.CONCLUSIONSThese results indicate that patients with VSA with significant coronary stenosis represent a high‐risk population despite current guideline‐recommended therapies, suggesting the importance of routine coronary functional testing in this population.

Acetylcholine provocation test with resting full-cycle ratio, coronary flow reserve, and index of microcirculatory resistance give definite answers and improve health-related quality of life.

Acetylcholine provocation test with resting full-cycle ratio, coronary flow reserve, and index of microcirculatory resistance give definite answers and improve health-related quality of life.

Pericoronary adipose tissue inflammation on coronary computed tomography in patients with vasospastic angina

Abstract Background A recent study has demonstrated that coronary spasm is associated with inflammation of peri-coronary adipose tissue (PAT) by using the combination of 18F-fluorodeoxyglucose positron emission tomography and computed tomography (CT). PAT attenuation (FAI) on CT angiography (CTA) has been reported to reflect PAT inflammation. We sought to investigate if FAI on CTA was associated with coronary vasospasm in patients with suspected vasospastic angina (VSA). Methods A total of 88 patients who underwent CTA and acetylcholine provocation test (SPT) for suspected VSA were retrospectively investigated. FAI was assessed by the crude analysis of the mean CT attenuation value of 3 major coronary arteries on CTA. FAI was evaluated for the proximal reference diameter (FAI-Ref) and inner 2mm adipose tissue layer (FAI-2mm) from the vessel wall. Diagnosis of VSA (VSA group) was made by SPT and the subjects with negative SPT without organic coronary lesions served as non-VSA group. Association between VSA diagnosis and FAI was assessed and the predictors of VSA was explored by univariable and multivariable analyses. Results In 45 patients (51.1%), VSA was diagnosed (VSA group). There were no significant differences in baseline characteristics between the VSA and non-VSA groups. RCA-FAI was significantly higher in patients of VSA group than in non-VSA group. RCA-FAI-2mm provided significantly better diagnostic performance for VSA than RCA-FAI-Ref and LCA-derived FAI values. Furthermore, RCA-FAI-2mm showed a significant relationship with the severity of spasm evaluated by most stenotic segment diameter during SPT. (r=−0.28, p&amp;lt;0.001) Multivariable logistic regression analysis revealed that RCA-FAI-2mm was an independent predictor of predicting VSA (P&amp;lt;0.001). Conclusion Coronary spasm may be linked with PAT inflammation detected by CTA-derived RCA-FAI, particularly by inner PAT assessment close to the vessel wall. Representative cases for FAI analyses Funding Acknowledgement Type of funding source: None

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

Comparison of clinical characteristics between patients with microvascular and epicardial coronary artery spasm

Abstract Background Coronary functional abnormalities including both epicardial and microvascular coronary artery spasm represent an important role responsible for myocardial ischemia in patients with angina and nonobstructive coronary artery disease. However, clinical characteristics associated with microvascular spasm (MVS) have not been fully evaluated. Purpose The aim of this study was to assess differences in clinical features between patients with MVS and epicardial coronary spasm. Methods A total of 732 consecutive patients with suspected angina who presented nonobstructive coronary arteries and underwent intracoronary acetylcholine provocation test were retrospectively enrolled in this study. Epicardial coronary spasm was defined as total or subtotal occlusion of epicardial coronary arteries accompanied by chest pain and/or ischemic electrocardiographic changes in response to acetylcholine provocation test. MVS was diagnosed when chest pain and/or ischemic electrocardiographic changes developed after administration of acetylcholine in the absence of epicardial coronary spasm. Clinical characteristics were compared between patients with MVS and epicardial coronary spasm. Results Of all patients, 83 patients (11%) had MVS, 367 (50%) had epicardial coronary spasm, and the other patients (39%) showed neither MVS nor epicardial coronary spasm. Patients with MVS tended to be older (65.6±12.7 vs. 63.0±12.3 years, P=0.088) and were more frequently female (60.2% vs. 41.1%, P=0.0016) in comparison with patients with epicardial coronary spasm. Patients with MVS were less likely to be smokers (8.6% vs. 22.9%, P=0.0018), while there were no significant differences in the other coronary risk factors such as hypertension, dyslipidemia, and diabetes mellitus. Serum uric acid were significantly lower in patients with MVS (4.9±1.1 vs. 5.4±1.3 mg/dl, P=0.0018). Conclusion Our study demonstrated that patients with MVS had distinctive clinical background from those with epicardial coronary spasm, suggesting different mechanisms may involve the development of MVS. 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

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

Beta blockers versus calcium channel blockers for provocation of vasospastic angina after drug-eluting stent implantation: a multicentre prospective randomised trial

BackgroundDrug-eluting stent-induced vasospastic angina (DES-VSA) has emerged as a novel complication in the modern era of percutaneous coronary intervention (PCI). Although beta blockers (BBs) are generally recommended for coronary heart...

Vasospastic angina and overlapping cardiac disorders in patients resuscitated from cardiac arrest.

Vasospastic angina (VSA) reportedly accounts for one form of sudden cardiac arrest (SCA). Intracoronary acetylcholine (ACh) testing is useful for diagnosing VSA although invasive provocation testing after SCA is a clinical challenge. In addition, even if the ACh test is positive, any causal relationship between VSA and SCA is often unclear because patients with VSA may have other underlying cardiac disorders. A total of 20 patients without overt structural heart disease who had been fully resuscitated from SCA were included. All patients underwent the ACh provocation test and scrutiny such as cardiac computed tomography or magnetic resonance imaging. Patients were followed up for all-cause death or recurrent SCA including appropriate implantable cardioverter defibrillator therapy. An ACh provocation test was performed 20 ± 17days after cardiac arrest. Fifteen out of 20 (75.0%) patients had a positive ACh test and 2 (10.0%) had adverse events such as ventricular tachycardia and transient cardiogenic shock during the test. In patients with a positive ACh test, 6 of 15 (40.0%) patients had other overlapping cardiac disorders such as long QT syndrome, Brugada syndrome, cardiac sarcoidosis, myocarditis, or cardiomyopathy. Long-term prognosis was not different regardless of a positive ACh test or the presence of other cardiac disorders overlapping with VSA. Three-quarters of the patients who had been resuscitated from SCA had a positive ACh test. Further examinations revealed other overlapping cardiac disorders in addition to VSA in 40% of patients with a positive ACh test.

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.

Dose-Response Relationship Between Intracoronary Acetylcholine and Minimal Lumen Diameter in Coronary Endothelial Function Testing of Women and Men With Angina and No Obstructive Coronary Artery Disease.

Intracoronary acetylcholine (Ach) provocation testing is the gold standard for assessing coronary endothelial function. However, dosing regimens of Ach are quite varied in the literature, and there are limited data evaluating the optimal dose. We evaluated the dose-response relationship between Ach and minimal lumen diameter (MLD) by sex and studied whether incremental intracoronary Ach doses given during endothelial function testing improve its diagnostic utility. We evaluated 65 men and 212 women with angina and no obstructive coronary artery disease who underwent endothelial function testing using the highest tolerable dose of intracoronary Ach, up to 200 μg. Epicardial endothelial dysfunction was defined as a decrease in MLD >20% after intracoronary Ach by quantitative coronary angiography. We used a linear mixed effects model to evaluate the dose-response relationship. Deming regression analysis was done to compare the %MLD constriction after incremental doses of intracoronary Ach. The mean age was 53.5 years. Endothelial dysfunction was present in 186 (68.1%). Among men with endothelial dysfunction, there was a significant decrease in MLD/10 µg of Ach at doses above 50 μg and 100 µg, while this decrease in MLD was not observed in women (P<0.001). The %MLD constriction at 20 μg versus 50 μg and 50 μg versus 100 μg were not equivalent while the %MLD constriction at 100 μg versus 200 μg were equivalent. Women and men appear to have different responses to Ach during endothelial function testing. In addition to having a greater response to intracoronary Ach at all doses, men also demonstrate an Ach-MLD dose-response relationship with doses up to 200 μg, while women have minimal change in MLD with doses above 50 µg. An incremental dosing regimen during endothelial function testing appears to improve the diagnostic utility of the test and should be adjusted based on the sex of the patient.

Decreased Double Product at Rest in Patients With Severe Vasospasm

Autonomic nerve system and endothelial function play important roles in vasospastic angina. Elevated heart rate (HR), blood pressure (BP), and double product (DP) can increase endothelial-dependent coronary artery dilation and blood flow. However, the impact of HR, BP, and DP on occurrence and severity of VSA in the clinical setting is unclear. A total of 170 patients undergoing intracoronary acetylcholine (ACh) provocation test during hospitalisation was included. Resting HR, BP, and DP were measured at least four times, and their variabilities were evaluated by standard deviations (SD) and coefficient of variations (CVs). Angiographic coronary artery vasospasm was defined as total or subtotal occlusion induced by ACh provocation. Mean±SD HR (65.7±9.1 vs 69.6±7.9 beats per minute; p=0.003), systolic BP (122.3±13.4 vs 127.7±14.6 mmHg; p=0.01), and DP (8,001±1,229 vs 8,903±1,495; p<0.001) were significantly lower in patients with a positive ACh test than the counterpart, whereas SD and CV of both HR and systolic BP were not significantly different between the two groups. Mean HR, BP, and DP progressively decreased with increase in the number of vessels with angiographic vasospasm. Multivariate analysis showed current smoking and lower DP as independent predictors of the greater number of vessels with provoked angiographic vasospasm. Resting HR, BP, and DP were lower in patients with vasospastic angina, especially in those with severe vasospasm.

Abstract 369: Implantable Cardioverter Defibrillator Therapy in Patients With Vasospastic Angina After Sudden Cardiac Arrest

Introduction: The prognosis of vasospastic angina (VSA) treated with optimal medication therapy is generally good. However, the patients resuscitated from sudden cardiac arrest (SCA) caused by lethal ventricular arrhythmias are at high risk of recurrent cardiovascular events. Moreover, little is known about the efficacy of implantable cardioverter defibrillator (ICD) therapy in this population The aim of this study is to evaluate the incidence of lethal arrhythmic events in VSA patients with secondary prophylaxis for SCA. Methods: Data from patients who received an ICD as a secondary prophylaxis in our institution between January 2012 and November 2018 were retrospectively analyzed. A total of 123 patients were enrolled in this study and divided into 16 patients with VSA (VSA group) and 107 patients without VSA (non-VSA group). VSA was diagnosed by acetylcholine provocation test or coronary angiography alone on arrival. Results: Current smoker was more prevalent and cardiac function was better in the VSA group. Diabetes mellitus was more prevalent in the non-VSA group. Although VSA patients were treated with calcium-channel blockers, with or without nitrates, 3 patients (18.8%) experienced appropriate ICD therapies due to lethal arrhythmias during a follow-up of 3.2 years. There were no significant differences in the proportion of appropriate and inappropriate therapy between 2 groups. (Table) Conclusions: Recurrent lethal arrhythmic events were common in patients with VSA after SCA. In addition to optimal medical therapy, ICD therapy should be aggressively considered in patients with VSA and a history of lethal arrhythmia.

Coronary Functional Abnormalities in Patients With Angina and Nonobstructive Coronary Artery Disease

BackgroundApproximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary stenosis, in whom coronary functional abnormalities could be involved. ObjectivesThis study examined the significance of coronary functional abnormalities in a comprehensive manner for both epicardial and microvascular coronary arteries in patients with angina and nonobstructive coronary artery disease (CAD). MethodsThis study prospectively enrolled 187 consecutive patients (male/female 113/74, 63.2 ± 12.3 years), who underwent acetylcholine provocation test for coronary spasm and measurement of index of microcirculatory resistance (IMR) to evaluate coronary microvascular function, and followed them for a median of 893 days. ResultsOf all subjects, acetylcholine test identified 128 patients with vasospastic angina (VSA) (68%), and cardiac events occurred in 10 patients (5.3%) during the follow-up. Multivariable analysis revealed that IMR correlated with the incidence of cardiac events (hazard ratio: 1.05; 95% confidence interval: 1.02 to 1.09; p = 0.002) and receiver-operating characteristics (ROC) curve analysis identified IMR of 18.0 as the optimal cut-off value. Among the 4 groups based on the cut-off value of IMR and the presence of VSA, the Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with high IMR (≥18.0) and VSA compared with other groups (log rank, p = 0.002). Importantly, intracoronary administration of fasudil, a Rho-kinase inhibitor, significantly ameliorated IMR in the VSA patients with increased IMR (p < 0.0001). ConclusionsThese results indicate that in patients with angina and nonobstructive CAD, coexistence of epicardial coronary spasm and increased microvascular resistance is associated with worse prognosis, for which Rho-kinase activation may be involved.

P5538Safety and efficacy of acetylcholine provocation test for diagnosis of vasospastic angina in young patients

Abstract Background Vasospastic angina (VSA) is considered as a cause of myocardial infarction with nonobstructive coronary arteries. Given the previous reports of higher incidence of cardiovascular events in young VSA patients, early diagnosis and optimal treatment are important for these patients. While acetylcholine provocation test (ACh test) for VSA diagnosis is well reported, ACh test among young patients is not as commonly performed, therefore its safety and usefulness for this patient subset have not been fully evaluated. Purpose The purpose of this study was to evaluate the safety and the proportion of positive results of ACh test for young patients. Methods Data from patients who underwent ACh test in our institution from May 2012 to September 2018 were retrospectively analyzed. A total of 669 patients were enrolled and divided into 2 groups according to age: Young group (Age≤50, n=106); and Senior group (Age&gt;50, n=563). Results The senior group had a higher incidence of hypertension, dyslipidemia, diabetes mellitus, and coronary artery disease. On the other hand, the young group had a significantly higher incidence of current smoker and tendency of daily alcohol. The rate of positive ACh test was similar, and there were no significant differences in major or minor complications between the 2 groups. Patient characteristics and outcome Young group Senior group p (n=106) (n=563) Age (years) 42.8±7.3 68.0±9.0 &lt;0.001 Male (%) 56.6 52.2 0.407 Current smoker (%) 34.9 15.4 &lt;0.001 Daily alcohol (%) 31.1 22.9 0.070 Hypertension (%) 33.0 66.6 &lt;0.001 Dyslipidemia (%) 50.0 68.4 &lt;0.001 Diabetes (%) 12.3 20.8 0.047 ACh positive (%) 52.8 49.9 0.581 Minor adverse event (%) 4.7 5.9 0.820 Major adverse event (%) 0.9 1.4 1.000 Major adverse event: composite of death, ventricular fibrillation, sustained ventricular tachycardia (VT), myocardial infarction and stroke. Minor adverse event: non-sustained VT and paroxysmal atrial fibrillation. Conclusion ACh provocation test for young patients can be safely performed, and the rate of positive results was similar to that of senior patients. In young patients suspected of having VSA, ACh test should be actively performed to identify optimal medical therapy for prevention of cardiovascular events. Acknowledgement/Funding None

P4158Marked impairment of endothelium-dependent digital vasodilatations in patients with microvascular angina compared with those with vasospastic angina

Abstract Background/Introduction Nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) factor are the major endothelium-derived relaxing factors. NO plays an important role in conduit arteries, while the importance of EDH factor increases as the vessel size decrease in patients with microvascular angina (MVA) compared with those with vasospastic angina (VSA) remains to be fully elucidated. Purpose We evaluated the roles of NO and EDH factor in conduit (brachial) arteries and resistance (digital) arteries of the patients with MVA, VSA and comorbid MVA+VSA patients. Methods We enrolled 39 patients who underwent diagnostic cardiac catheterization and divided them into 3 groups based on acetylcholine (ACh) provocation test, index of microcirculation resistance (IMR), and coronary flow reserve (CFR); MVA (N=9, mean age 59.9±3.5 years), VSA (N=12, mean age 61.3±1.8 years), and comorbid MVA+VSA (N=18, mean age 64.0±2.2 years). Endothelium-dependent brachial and digital vasodilatations in response to intra-arterial infusion of bradykinin (BK, 25, 50, and 100 ng/min for 2 min) were simultaneously measured by ultrasonography and peripheral arterial tonometry, respectively. Measurements were repeated after oral administration of aspirin (486 mg) and intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, 8μmol/min for 5 min) in order to inhibit the effects of vasodilator prostaglandins and NO, respectively. Finally, endothelium-independent brachial and digital vasodilatations in response to sublingual nitroglycerin (NTG, 0.3 mg) were measured in the same manner. Results In the brachial artery, dose-dependent vasodilatations to BK were comparable among the 3 groups, and L-NMMA equally attenuated the responses to BK (Figure 1). Endothelium-independent brachial vasodilatation in response to NTG was also comparable among the 3 groups. Surprisingly, dose-dependent digital vasodilatations to BK were almost absent in MVA patients compared with VSA or comorbid MVA+VSA group (Figure 2). Furthermore, the digital vasodilatations were unaffected by L-NMMA in VSA group, but were significantly reduced in comorbid MVA+VSA group (VSA, 16.8±15.1% vs. MVA+VSA, −0.23±6.2%, P&lt;0.05), suggesting reduced EDH and compensatory role of NO in the latter group. In contrast, endothelium-independent digital vasodilatation in response to NTG was comparable among the 3 groups. The main results of this study Conclusions These results provide the first evidence that endothelium-dependent digital vasodilatations (both NO and EDH factor) are markedly impaired in MVA patients compared with VSA or comorbid MVA+VSA patients, whereas the responses are comparable in the brachial artery among the 3 groups, suggesting the involvement of severe endothelial dysfunction in the pathogenesis of MVA.

P4156Coexistence and prognostic impacts of epicardial and microvascular coronary dysfunctions in patients with chest pain and unobstructive coronary artery disease - Involvement of Rho-kinase activation

Abstract Background Although the importance of coronary functional abnormalities has been emerging, including epicardial coronary spasm (vasospastic angina, VSA) and coronary microvascular dysfunction (CMD), comprehensive evaluation of the abnormalities in the same population remains to be examined. Purpose We examined the significance of coronary functional abnormalities in a comprehensive manner for both epicardial and microvascular coronary arteries in patients with chest pain and unobstructive coronary artery disease (CAD) as well as their prognostic impacts. Methods and results We prospectively enrolled 187 consecutive patients with suspected angina and unobstructive coronary arteries (M/F 113/74, 63.2±12.3 [SD] yrs.). We performed acetylcholine (ACh) provocation tests for coronary spasm, followed by functional tests for coronary microvascular function, including coronary flow reserve (CFR) and index of microcirculation resistance (IMR) during hyperemic state induced by intravenous adenosine. Among the 187 patients, ACh test identified 128 patients with VSA (68%). There was no significant difference in age, sex, or prevalence of traditional coronary risk factors between the non-VSA and the VSA groups. The median IMR value was significantly higher in the VSA group than in the non-VSA group [17.5 (12.0, 25.3) vs. 14.7 (10.7, 17.8), P=0.02], whereas CFR values were comparable between the 2 groups [2.51 (1.72, 3.35) vs. 2.66 (1.85, 3.64), P=0.34]. During the median follow-up period of 893 days, major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, and hospitalization due to unstable angina pectoris, occurred in 10 patients (5.3%). Multivariable analysis revealed that IMR correlated with the incidence of MACE [hazard ratio (HR) (95% confidence interval), 1.05 (1.02–1.09), P=0.002] and receiver-operating characteristics curve analysis identified IMR of 18.0 as the optimal cut-off value for the incidence of cardiac events. When we divided the patients into the following 4 groups according to the cut-off value of IMR (&gt;18) and the presence or absence of VSA; G1, IMR &lt;18 without VSA (n=45); G2, IMR ≥18 without VSA (n=14); G3, IMR &lt;18 with VSA (n=67); and G4, IMR ≥18 with VSA (n=61), the Kaplan-Meier survival analysis showed a significantly worse prognosis in G4 compared with other 3 groups (HR [95% CI] 6.23 [1.21–118.46], P=0.002) (Figure 1). Importantly, intracoronary administration of fasudil, a Rho-kinase inhibitor, significantly ameliorated IMR in G4 (P&lt;0.0001) (Figure 2A), and %changes in IMR in response to intracoronary fasudil were more evident in G4 compared with other 3 groups (P&lt;0.0001) (Figure 2B). Conclusions These results provide the first evidence that in patients with chest pain and unobstructive CAD, epicardial coronary spasm and increased microvascular resistance are frequently coexisted with worse long-term prognosis, for which Rho-kinase activationmay be involved.

P3575Clinical importance of fractional flow reserve in patients with organic coronary stenosis and vasospastic angina

Abstract Background Vasospastic angina (VSA), which is one of the important functional cardiac disorders, may also play a role in the pathogenesis of atherosclerosis. Conversely, organic coronary stenosis is also known as an independent predictor for poor clinical outcomes in VSA patients. Although VSA patients have a variable degree of organic coronary stenosis in clinical setting, the functional importance of organic stenosis in those patients remains to be elucidated. Purpose The aim of this study was to examine the clinical importance and prognostic impact of fractional flow reserve (FFR) in patients with VSA and organic coronary stenosis. Methods We enrolled 236 consecutive patients with suspected vasospastic angina who underwent acetylcholine provocation test for coronary spasm (M/F 148/88, 63.6±12.0 [SD] yrs.). Among them, 175 patients (74.1%) were diagnosed as having VSA, while the remaining non-VSA patients were regarded as controls (Group-C, n=61). We divided the VSA patients into 3 groups based on angiographical findings and FFR values; VSA with no organic stenosis (&gt;50% luminal stenosis) (Group-N, n=110), organic stenosis and high FFR (≥0.80) (Group-H, FFR 0.87±0.05, n=36), and organic stenosis and low FFR (&lt;0.80) (Group-L, FFR 0.71±0.07, n=29). We evaluated the incidence of major adverse cardiovascular events (MACE), including cardiovascular death (CVD), non-fatal myocardial infarction (MI), urgent percutaneous coronary intervention (PCI), and hospitalization due to unstable angina pectoris (UAP) during the median follow-up period of 656 days. Results The groups with organic stenosis (Groups H and L) were characterized by higher prevalence of diabetes mellitus (Group-C/N/H/L, 23.0/20.9/44.4/34.5%, P=0.03) and dyslipidemia (Group-C/N/H/L, 37.7/39.1/50.0/65.5%, P=0.03) as compared with Group-C. After provocation test, all VSA patients received calcium channel blockers (CCBs). In addition, 20 days (median) after provocation test, 26 patients (92.9%) in Group-L underwent elective PCI with coronary stents, while no patient underwent PCI in Groups N or H. The incidence of MACE during follow-up was significantly higher in Group-L (Group-C/N/H/L; 1.6/3.6/5.6/27.6%, log-rank P&lt;0.001), whereas clinical outcomes were comparable among the remaining 3 groups (Figure). Importantly, all 8 patients with MACE in Group-L had poor outcomes (CVD/MI/urgent PCI/UAP; 2/1/3/2) despite complete revascularization and the prevention of coronary spasm with CCBs, indicating that they might be resistant to standard contemporary therapies. They were characterized by less frequent use of angiotensin convert enzyme inhibitor (0 vs. 47.6%, P=0.02) and higher prevalence of multi-vessel organic lesions (37.5 vs. 4.8%, P=0.052) compared with those without MACE. Figure 1 Conclusions These results provide the first evidence that evaluation of coronary functional abnormalities with FFR is useful for making therapeutic strategies in VSA patients with organic coronary stenosis.

P6004Safety assessment and results of coronary spasm provocation testing in patients with MINOCA compared to patients with stable angina and unobstructed coronary arteries

Abstract Background Approximately 10% of patients with acute myocardial infarction do not have a culprit lesion. Such patients have been labelled as MINOCA (myocardial infarction with non-obstructive coronary arteries) and several pathophysiological etiologies have been described as potential explanations. This includes spontaneous coronary dissection, tako-tsubo-syndrome and coronary spasm. The latter can be diagnosed during invasive provocative testing. The aim of this study was to assess the frequency of coronary spasm and the safety of intracoronary provocation testing using acetylcholine in MINOCA patients compared to patients with stable angina and unobstructed coronary arteries. Methods Between 2007 and 2018 180 consecutive patients with either MINOCA or stable angina and unobstructed coronary arteries were enrolled. MINOCA was defined as acute onset of chest pain with either ST-segment elevation on the ECG or significant high sensitive troponin T elevation but no relevant epicardial stenosis (&lt;50%) according to the current ESC guidelines. All patients underwent intracoronary acetylcholine provocation testing (ACH-test) in search of coronary spasm according to a standardized protocol immediately after diagnostic coronary angiography. Apart from systematic assessment of clinical, demographic and risk factor data, data regarding complications during the ACH-test were meticulously recorded. Results Eighty patients with MINOCA and 100 consecutive patients with stable angina were recruited (52% women, mean age 62±13 years). Overall, 59% had hypertension and 20% had diabetes. Comparison of clinical, demographic and risk factor data did not reveal any statistically significant differences except for a female preponderance in the stable patients (61% vs. 40%, p=0.007). The ACH-test revealed a coronary vasomotor disorder in 68% of cases. In 32% of cases the ACH-test was either inconclusive or negative. Epicardial spasm was found in 31% of patients with a higher prevalence among the MINOCA patients compared to the stable angina patients (41% vs. 23%, p=0.002). Microvascular spasm was found in 37% with a higher prevalence among the stable angina patients compared to the MINOCA cohort (49% vs. 23%, p=0.002). Assessment of complications during the ACH-test revealed that 13 MINOCA patients and 15 stable angina patients had minor complications such as intermittent atrioventricular block, sinusbradycardia, paroxysmal atrial fibrillation, ventricular ectopic beats or transient hypotension. Comparison of minor complications between the two groups did not reveal statistically significant differences (16% vs. 15%, p=0.839). None of the patients experienced any irreversible complications. Conclusion Coronary spasm is a frequent cause for MINOCA. Intracoronary spasm provocation testing using acetylcholine is feasible in such patients. The complication rate during ACH-testing in MINOCA patients is low and comparable to patients with stable angina. Acknowledgement/Funding Berthold-Leibinger-Foundation, Ditzingen, Germany

P3648Plasma glutamate are increased in non-smoker patients with vasospastic angina pectoris and associated with plasma cystine and antioxidant capacity

Abstract Background Endothelial dysfunction of the coronary arteries caused by oxidative stress plays an important role in the pathogenesis of vasospastic angina pectoris (VSAP). Glutamate, a non-essential amino acid, exerts endothelial dysfunction by oxidative stress production through N-methyl-D-aspartate receptor activation. Besides oxidative stress, decrease of antioxidant may be responsible for endothelial dysfunction. Glutathione (GSH), an important antioxidant, is synthesized from imported cystine through the cystine/glutamate antiporter system (XC-) in association with the export of glutamate. Glutamate also competitively inhibits cystine import into the endothelial cells through the XC-leading to GSH depletion. Thus the extracellular glutamate and cystine are crucial for the intracellular redox status. However, it remains unclear whether glutamate and/or cystine are implicated in the pathogenesis of VSAP. As smoking induces powerful oxidant stresses in the whole body, we investigated plasma glutamate, cystine, oxidative stress markers and antioxidant capacity in non-smoker patients with VSAP. Methods and results Sixty-two consecutive non-smoker patients suspected having VSAP were performed coronary angiograms (CAG). Forty-nine patients who did not show any significant coronary stenosis (&lt;50%) were performed the intracoronary acetylcholine provocation test. Patients were categorized into the VSAP-positive group (n=27) and the VSAP-negative group (n=22) on the basis of test results. Blood samples were collected from the femoral sheath before the CAG. Plasma glutamate, cystine, nitrotyrosine (NT), reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) were measured. The levels of plasma glutamate and cystine in the VSAP-positive group were significantly higher than those in the VSAP-negative group (59.8±25.7 vs 43.5±18.7 nmol/L, p=0.0054, and 35.3±14.2 nmol/L vs 25.2±9.1 nmol/L, p=0.0018, respectively). The levels of plasma glutamate showed significant and positive association with the levels of plasma cystine (r=0.40, p=0.005). There were no significant differences in the levels of NT and d-ROMs as oxidative stress markers, and BAP as an antioxidant capacity between the two groups, respectively. However, the levels of plasma glutamate showed significant and negative association with BAP values (r=−0.3, p=0.038). Conclusions Plasma levels of glutamate were increased in non-smoker patients with VSAP and positively associated with plasma cystine levels and negatively associated with antioxidant capacity, suggesting that plasma glutamate modulate plasma cystine levels and antioxidant capacity through the XC- inhibition, and could be a novel risk factor of VSAP.