Provocation Test Research Articles

Early recurrence of spontaneous coronary artery dissection: potential association with coronary vasospasm and optimal timing for spasm provocation test - a case series

Abstract Background Spontaneous coronary artery dissection (SCAD) is an uncommon cause of acute coronary syndrome (ACS). Various factors predispose individuals to SCAD, including coronary vasospasm, which has been identified in some studies as a related factor. Case summary We present a series of three cases of ACS attributed to SCAD. Two cases involved early de novo recurrence potentially related to coronary spasm, and one case involved iatrogenic coronary artery dissection during a spasm provocation test. Discussion High recurrence rates of SCAD within 30 days of the initial event have been observed, although the effectiveness of pharmacologic therapy has not been conclusively established. While the administration of beta-blockers has been associated with a reduced risk of SCAD recurrence, their use may not be desirable in patients with coronary vasospasm. Detailed evaluations may be beneficial for patients where coronary vasospasm is suspected to tailor appropriate treatment strategies. Moreover, given the higher frequency of iatrogenic coronary artery dissection among patients with SCAD, careful consideration is needed to avoid high-risk periods when scheduling spasm provocation tests.

Eating increases disease activity in pediatric patients with symptomatic dermographism

Background: Symptomatic dermographism (SD) is the most common form of chronic inducible urticaria. SD disease activity increases with food intake in adult patients. Whether this is also so in children with SD is currently unknown. Objective: To assess children with SD for their disease activity by standardized provocation testing before and after eating. Methods: We subjected 44 children with SD (29 girls; median [interquartile range] age 12.5 years [8.3‐15 years]), before and after eating, to standardized skin provocation testing with a dermographometer. Dermographometer scores were calculated based on responses evaluated at 1-minute intervals for 10 minutes and recorded as negative (‐) or positive (+ to ++++). Clinical characteristics and urticaria control test scores were documented. Results: Dermographometer scores before eating were 2.3 of 4 on average and inversely correlated with urticaria control test scores. Dermographometer scores were higher after eating than before eating. Of 44 children with SD, 35 had increased dermographometer scores after eating and 9 patients had a postprandial increase of ≥1 point. Eating-induced increases in dermographometer scores were linked to earlier whealing in 17 of 35 patients, and differences in preprandial versus postprandial dermographometer responses were more pronounced at earlier than later time points after testing. Conclusion: Disease activity, as assessed by provocation testing, is increased in most pediatric patients with SD after eating. Future studies should explore the prevalence of food-exacerbated SD in larger pediatric SD populations. Most pediatric patients with symptomatic dermographism have higher disease activity, assessed by provocation testing, after eating as compared to before eating. Standardized provocation testing and trigger threshold assessments in children with symptomatic dermographism should be performed before and after eating. Knowledge of food-exacerbated disease may help patients with the management of their symptomatic dermographism.

Effects of radial artery spasm prophylaxis on intracoronary vasomotor responses during acetylcholine spasm provocation testing

BackgroundInvasive coronary angiography via the radial approach is commonly performed following radial artery spasm prophylaxis (RASP). It is however unknown, whether RASP influences the results of coronary spasm provocation testing performed after diagnostic angiography. We aimed to investigate the effects of RASP on vasomotor responses during intracoronary acetylcholine (ACh) testing. MethodsWe retrospectively screened 372 consecutive patients (51 % female, mean age 61 ± 11 years) with angina and non-obstructive coronary arteries, who underwent intracoronary provocation with ACh according to a standardized protocol. During testing, dose-dependent clinical discomfort and concomitant ischemic electrocardiographic changes were recorded in addition to visual reductions of epicardial lumen diameters. Of these patients, 156 (42 %) received RASP (i.e. 200 μg nitroglycerin and 2.5 mg verapamil), while no RASP was administered in 216 (58 %) patients. Both groups were compared regarding age, sex, cardiovascular risk factors and ACh-test results. ResultsACh provocation testing revealed a pathological test result in 71 patients (46 %) with RASP and 103 patients (48 %) without (p = 0.752) [epicardial spasm: in 20 patients (28 %) with RASP and 42 patients (41 %) without (p = 0.120); microvascular spasm: in 51 patients (72 %) with RASP and 61 patients (59 %) without (p = 0.362)]. Overall, RASP did not significantly alter coronary artery vasomotor responses, neither regarding the frequency (p = 0.752) or type of coronary spasm (microvascular vs. epicardial; p = 0.108) nor regarding the ACh dose leading to spasm (p = 0.151). ConclusionsRASP does not significantly affect coronary vasomotor responses to ACh, suggesting that radial artery spasm prophylaxis can be routinely administered even in patients in whom intracoronary spasm testing is performed.

Assessment of pediatric patients with suspected nonsteroidal anti-inflammatory drug hypersensitivity

Background: Beta-lactam antibiotics are the most common cause of hypersensitivity reactions to medications, followed by nonsteroidal anti-inflammatory drugs (NSAID). Objective: The aim of this study was to classify children with hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAID-H) according to the latest updates. Methods: ENDA recommendations were used to evaluate all patients with suspected NSAID-H. Children were classified as either selective responders (SR) or cross-intolerant based on the results of the drug provocation test (DPT). Results: Sixty-seven patients with suspected NSAID-H were evaluated in this study. NSAID-H was confirmed in 20 patients (29.9%). Among the 20 patients diagnosed with NSAID-H, 15 were classified according to the 2018 EAACI/ENDA Position Paper. Twelve patients (80%) were classified as cross-intolerant and 3 (20%) as SRs. NSAID-H was confirmed in 4 of 37 patients (10.8%) ages <10 years and 16 of 30 patients (53.3%) ages >10 years (p < 0.001). Twelve patients ages >10 years were classified. Cross-intolerance was detected in nine patients (66.6%). In patients >10 years of age, NSAID-induced urticaria/angioedema (NIUA) (16.7%) was the most common type in the group with classifiable cross-intolerant. In addition, NSAID-exacerbated respiratory disease was detected in one patient. Conculsion: Ibuprofen is the most common NSAID-H drug used in children. NIUA is the most common reaction. In pediatric allergy, hypersensitivity to NSAIDs is a challenging diagnostic issue. Hypersensitivity to NSAIDs poses a challenging diagnostic issue in pediatric allergies. The oral challenge test is the main diagnostic tool; however, in clinical practice, performing multiple challenge tests is difficult.

The safety of initial single therapeutic dose challenge with a 5-day prolonged drug provocation test in children with a history of low-risk non-immediate reactions to beta-lactam antibiotics

Background: Although the gold standard for diagnosing beta-lactam antibiotic (BLA) allergy is the drug provocation test (DPT), there is no standardized protocol for children. Objective: We aimed to evaluate the clinical features and DPT results of children with a history of low-risk non-immediate reactions (NIR) to BLA who underwent initial direct single therapeutic dose challenge with a 5-day prolonged DPT. Methods: We retrospectively evaluated children ages 0‐18 years with a history of low-risk NIRs to BLAs. On the first day of provocation, a single-dose DPT protocol without any skin test was administered at the clinic. The therapeutic dose was adjusted to not exceed the maximum single-unit dose (MSUD) for age and weight. The DPT protocol was administered with 100% of MSUD. To identify children with delayed reactions, the parents or caregivers were told to continue giving the medication at home for 5 days. Results: One hundred and nine children were included in this study. The median (interquartile range) age of the children was 62.5 months (26.5‐94 months). Of the suspected drugs, the main culprit drug was amoxicillin-clavulanic acid for 89 children (81.7%). The most common clinical manifestation was maculopapular exanthema, which occurred in 85 children (78%), and 8 (7.3%) had a positive DPT result. Three children (2.8%) developed a reaction after the first DPT dose. The remaining children continued to use the suspected BLA at home. Five children (4.7%) developed a reaction while using the drug at home. All the children with positive DPT results developed mild cutaneous signs and presented with a reaction to amoxicillin-clavulanic acid. None had a systemic or severe cutaneous reaction. Conclusion: Initial direct single therapeutic dose challenge with a 5-day prolonged DPT is a useful and safe way to assess low-risk NIRs to BLAs in children.

The effect of 30 min of supine rest on plasma renin concentrations in paediatric patients.

The aim of this study is to interpret plasma renin concentrations (PRCs) correctly in a clinical setting, it is essential to understand to what extent physical activity influences the concentration. Reference values for different postural positions exist for adults, but data for children are sparse. In this study, the effect of 30 min of rest on plasma renin concentrations in paediatric patients was examined. In total, 41 paediatric patients, undergoing either arginine or clonidine provocation tests for growth hormone deficiency, were included. For each stimulation test, two blood samples were drawn. One at time 0 min and one after 30 min of rest. In total, renin concentrations were determined in 86 serum samples. Renin concentrations decreased from 0 to 30 min with a median value of -20.5% (inter-quartile range: -33.0% to -12.8%). This decrease was not dependent on sex, age, medication or comorbidity, and the variance of renin did not differ between 0 and 30 min. Renin concentrations in children differ according to postural position, which is comparable to adults. Thus, the clinical interpretation of renin results needs to consider the preanalytical conditions applied in the local reference population.

Evaluating serum periostin and YKL-40 as biomarkers for airway remodeling and hyperresponsiveness in pediatric asthma

BackgroundPeriostin and human chitinase-3-like protein 1 (YKL-40) have been suggested to be involved in the development of airway fibrosis and remodeling. This study aimed to investigate the relationship between serum periostin levels and airway hyperresponsiveness (AHR) and between serum YKL-40 levels and AHR in children with asthma, comparing periostin as a marker for Th2 inflammation and atopy with YKL-40. MethodsThe study involved children aged 6–15 years, comprising 75 with asthma and 29 healthy controls. We measured serum periostin and YKL-40 levels and performed exercise bronchial provocation tests, methacholine challenge tests, spirometry, and FeNO measurements. ResultsCompared to the healthy controls, asthmatic children exhibited significantly elevated levels of periostin (86.7 [71.0–104.0] vs 68.3 [56.0–82.0] ng/mL; P = 0.006) and YKL-40 (29.0 [15.0–39.5] vs 27.7 [14.0–34.1] ng/mL; P = 0.034). The subgroup analysis revealed that periostin levels were significantly higher in the atopic asthma group than in the healthy controls (P = 0.003), but not in the non-atopic asthma group. YKL-40 levels were elevated in both the atopic and non-atopic asthma groups compared to healthy controls (P = 0.012 and P = 0.001, respectively). Serum periostin levels were significantly correlated with the postexerceise maximum percentage decrease in forced expiratory volume (FEV1), as well as with fractional exhaled nitric oxide (FeNO) and blood eosinophil counts, but showed no significant correlation with overall lung function. Conversely, serum YKL-40 levels were significantly linked to the Z score of FEV1 and AHR to methacholine but not with AHR to exercise or FeNO or blood eosinophil count. ConclusionsPeriostin is linked to atopic asthma and correlates with exercise-induced bronchoconstriction, FeNO, and eosinophil counts, highlighting its role in Th2 inflammation. YKL-40 is a general asthma marker, indicating airway remodeling. These findings suggest that targeting these markers can improve personalized treatment strategies for pediatric asthma.

Additional Diagnostic Yield of the Rapid Drink Challenge in Chicago Classification Version 4.0 Compared With Version 3.0.

Chicago classification version 4.0 enhances the diagnosis of esophageal motility disorders using position change and provocative tests such as multiple rapid swallows and a rapid drink challenge. This study investigates the diagnostic role of the rapid drink challenge based on Chicago classification 4.0 using a functional luminal imaging probe to estimate the cutoff value. This study included 570 patients who underwent esophageal manometry with a rapid drink challenge between January 2019 and October 2022. The diagnostic flow was analyzed according to Chicago classification 4.0. Ninety-nine patients (38, achalasia; 11, esophagogastric junction outflow obstruction; 7, ineffective esophageal motility; 1, hypercontractile esophagus; and 42, normal esophageal function) failed the rapid drink challenge. Among the 453 participants, 50 and 86 were diagnosed with achalasia and esophagogastric junction outflow obstruction, respectively, using Chicago classification 4.0. In 249/453 (55.0%) patients initially diagnosed with esophagogastric junction outflow obstruction using Chicago classification 3.0, the diagnosis was changed to achalasia (n = 28), hypercontractile esophagus (n = 7), ineffective esophageal motility (n = 7), or normal esophageal function (n = 121) using Chicago classification 4.0. Rapid drink challenge-integrated relaxation pressure's diagnostic cutoff value was 19 mmHg. Nine patients had diagnoses changed after the rapid drink challenge, including 3 with panesophageal pressurization. Chicago classification 4.0 increased the diagnostic yield of the rapid drink challenge by 2.0% (9/453 patients). However, the rapid drink challenge had a failure rate of 17.9% (99/552 patients). Given the relatively low diagnostic yield and high failure rate of the rapid drink challenge, we recommend adopting an individualized approach to manometry.

Preoperative Embolization of Brain Tumors Using a Provocative Test: Evaluating the Safety and Efficacy of Embolization of Test-Positive Vessels

Preoperative Embolization of Brain Tumors Using a Provocative Test: Evaluating the Safety and Efficacy of Embolization of Test-Positive Vessels

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.

Coronary physiology: no complete diagnosis without acteylcholine

Abstract Introduction In up to 40% of patients with pectanginous symptoms, no obstructive coronary artery disease (NOCAD, no stenosis > 50%) can be detected as the cause, so that the terms ANOCA (angina with no obstructive CAD) or INOCA (ischemia with no obstructive CAD) have been defined. In patients with acute myocardial infarction, 5-20% are diagnosed with MINOCA (myocardial infarction with no obstructive CAD). Microvascular dysfunction (CMD) or coronary spasm has been identified as one of the leading causes of these entities. Further clarification by determining the coronary flow reserve (CFR) an microvascular resistance (IMR) is used to diagnose CMD and is also included in the ESC guidelines. The indices can be determined using thermodilution or ultrasound/doppler wires methods. According to current recommendations, the acteylcholine provocation test is administered in cases of suspected coronary spasm. Despite extensive studies on the safety of ACh testing, many clinics refrain from testing for vasoconstriction disorder although microvascular coronary spasm has been shown to be the leading subgroup of CMD in registry studies. Purpose We want to investigate the necessity of a complete coronary physiological examination, consisting of CRF/IMR and ACh provocation test, when compared to testing without ACh. Methods All 299 patients who underwent complete physiological testing in our clinic between 2021 and 2024 due to ANOCA, INOCA or MINOCA were evaluated retrospectively. Patients completed a coronary physiological examination using thermodilution and an acetylcholine provocation test. The IMR, CFR, fractional flow reserve (FFR), resting full-cycle ratio (RFR) and the ACh test (defined as epicardial spasm >90% reduction in coronary diameter with symptoms and/or ischemic electrocardiographic changes, respectively no epicardial spasm >90% reduction in coronary diameter with symptoms and and ischemic electrocardiographic changes for microvascular spasm) are thus routinely measured. Results Of the total of 299 patients included, 244 (81%) were found to have impaired vasoconstriction with pathologic ACh testing, either alone or in combination with pathologic indices CFR/IMR. The leading finding of pathological spasms was microvascular coronary spasm (66%). 119 patients with normal CFR/IMR had a diagnosis of microvascular (72 patients) or macrovascular spasm (47 patients). 40% of the total patient cohort would have not had a compete diagnosis without the use of Ach testing. Conclusion Physiological testing without the systematic use of ACh testing will misdagnose a significant amout of patients with ANOCA/MINOCA/INOCA. ACh testing should be always performed to complete the diagnosis for these patients

Myocardial Bridging: a bridge to spasm?

Abstract Introduction Myocardial bridges (MBs) represent a congenital anomaly where a segment of a coronary artery passes through the myocardium, resulting in systolic compression. The role of MBs in causing chest pain has been debated, as coronary blood flow occurs primarily in diastole. MBs are generally considered benign, there is growing evidence implicating them in the pathogenesis of coronary artery spasm (CAS). However, the prevalence of CAS in patients in Europe with MBs, particularly assessed through acetylcholine (ACh) testing, remains poorly defined. Methods We conducted a retrospective analysis of consecutive patients with angina with no obstructive CAD (ANOCA), ischemia with no obstructive CAD (INOCA), or myocardial infarction with no obstructive coronary arteries (MINOCA) undergoing ACh testing between 2021 and 2024 at our centre. Patients with documented MBs on coronary angiography were included. The presence of epicardial CAS, defined as >90% reduction in coronary diameter with symptoms and/or ischemic electrocardiographic changes, was assessed during ACh provocation testing. Clinical characteristics, Fractional flow reserve (FFR), resting full-cycle ratio (RFR), coronary flow reserve (CFR) and the index of microvascular resistance (IMR) were also analyzed. Results From a total of 299 patients who underwent ACh Testing, 21 patients were identified with MBs, (17 Male, 4 Female). The prevalence of focal CAS in the MB among these patients was 90%. None of these patients had abnormal hyperemic (FFR) or non-hyperemic (RFR) measurements. 9 of the 21 patients with MB had increased IMR, and only 1 had a CFR < 2. 1 Patient had both microvascular CAS in addition to focal epicardial CAS. Conclusion This analysis provides valuable insights into the prevalence of CAS in patients with MBs undergoing ACh testing. The findings underscore the importance of considering CAS in the evaluation and management of patients with MBs, particularly during provocative testing. Further prospective studies are warranted to validate these findings and elucidate the clinical implications for risk stratification and treatment strategies in this patient population.

Phenotype heterogeneity of SCN5A mutations in Brugada syndrome

Abstract Introduction Although SCN5A is the main gene associated with Brs syndrome (Brs), rare variants in this gene only affect 20 to 30 % of patients. Additionally, associated phenotype may differ even among relatives sharing the same mutation emphasizing a phenotype heterogeneity that is poorly understood for now. Objective Here we aim to investigate the association between the presence of SCN5A mutations and the expression of a BrS phenotype in large families. Methods Among Brugada patients enrolled in our prospective cohort, we included patients from families with affected proband carrier of a SCN5A mutation and at least 4 relatives carriers of the same SCN5A mutation. Patient without a spontaneous type 1 ECG and no pharmacological provocative test were excluded. Results A total of 463 individuals from 45 large families were enrolled. Among them, 258 (56%) were mutation carriers of one of the 33 identified SCN5A mutations. After pharmacological test, 219 (47%) individuals were diagnosed with BrS, including 32 not carriers of the familial mutation. Seventy-five patients (30%), carriers of the familial SCN5A mutation, remain negative for Brugada syndrome after pharmacological test. The prevalence of genotype-phenotype mismatch was 24%, including 32 BrS patients non carrier of the familial mutation (phenocopy) and 75 patients with the familial mutation but without BrS (30% of uncomplete penetrance). Conclusion Our data strongly suggest that SCN5A mutation is not either necessary nor sufficient to explain the occurrence of BrS phenotype. We now aim to identify which associated factors might interfere, focusing first on the genetic background of phenotype/genotype mismatched individuals.

Long-term validation of AtherosSlerosis CardioVascular Disease (ASCVD) risk score and the role of aspirin for primary Cardiovascular prevention in Korean patients with over ASCVD 20% risk score

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death worldwide. The ASCVD risk score can be a great tool for preventing ASCVD in the future. There is a mediation recommendation depending on calculated risk called United States Prevention Services Task Force (USPSTF) aspirin (ASA) recommendation. However, the validation studies of long-term clinical outcomes in Korean population using the ASCVD risk score and of the effect of ASA in Korean patients using USPSTF recommendation are limited. Methods A total of 7,249 patients with any chest pain who underwent coronary spasm provocation tests between January 2004 and December 2021 were enrolled. Patients were divided into four groups, based on the ASCVD risk score: < 5% group (Low Risk, n = 2,534), 5 - 10% group (Borderline Risk, n=1,681), 10 - 20% group (Intermediate Risk, n = 1,896) and ≥ 20% group (High Risk, n = 1,138). The primary endpoint was Major Adverse Cerebral and Cardiovascular Event (MACCE1), including stroke and MACE. The secondary endpoint was MACCE 2, defined as composite of MACE and recurrent angina requiring follow-up coronary angiography (CAG). The third endpoint was the effect of aspirin in patients who have over 20% ASCVD risk. Results Long term (10-year) ASCVD risk score was well-validated from the "Low Risk" group to the "High Risk" group by 1.87%, 7.44%, 14.09%, and 30.61%, respectively (P < 0.001). In baseline characteristics, the calculation factors of ASCVD risk score is also well-stratified, showing the more adverse clinical profiles in the "High Risk" group than the "Low Risk" group. In 10-year clinical outcomes, although MACCE1 and MACCE2 showed an increasing trend numerically, stroke was observed to significantly increase according to ASCVD risk score. There was no effect of ASA prescribed in accordance with USPSTF recommendation. The group with the highest rate of 20% or more failed to show the aspirin prevent effect on the occurrence of CV events, but also increased the incidence (MACCE1; HR: 1.647, P-Value: 0.283, 95% CI: 0.662 - 4.100, MACCE2; HR: 1.819, P-Value: 0.025, 95% CI: 1.078 - 3.068). Conclusion Long term ASCVD risk score was associated with higher risk of stroke. However, MACCE1 and MACCE2 only showed an increasing trend numerically. Furthermore, the effect of ASA prescribed based on the USPSTF ASA use recommendation statement were not observed in Korean population. Consequently, additional research is needed to ensure the utility of ASCVD risk score and the effect of ASA in high-risk patients to prevent future CV events in Korean population.

Association between lipoprotein-associated phospholipase A2 gene Val279Phe homozygous genotypes and variant angina in Japanese women

Abstract Background The role of the lipoprotein-associated phospholipase A2 gene (PLA2G7) in the pathogenesis of cardiovascular diseases remains controversial. The PLA2G7 gene normally produces a protein called "plasma platelet activating factor-acetylhydrolase"(PAF-AH). Homozygotes of rs76863441, which is PLA2G7 Val279Phe polymorphism, produce none of PAF-AH, and heterozygotes produce less than half of the normal levels. This polymorphism is rare outside of Asia and is particularly common in Japan, where homozygous mutations account for 4% of the population. The association between rs76863441 and risk of myocardial infarction was significant in ethnicity for Japanese population, but not in other countries. Variant angina is a severe case of coronary artery spasm (CSA) and causes an acute myocardial infarction. It is widely accepted that variant angina is more common in Japanese than in other races. Purpose The aim of this study was to examine the possible association between rs76863441 and variant angina. Methods rs76863441 was analyzed by direct sequencing in 62 patients with variant angina (43 men and 19 women with a mean age of 60.0±11.6 years). In all patients, ST segment elevation was recorded on ECG and coronary angiography was performed. Acetylcholine provocation test was performed in 31 patients. We compared genotypes of rs76863441 between variant angina patients and 872 healthy volunteers without a history of heart diseases living in the same area, who participated in the Iwaki Health Promotion Project, which has been conducted by the Hirosaki University School of Medicine since 2005. These volunteers had undergone Japonica Arrays, which is the SNP array for the Japanese population. Results Homozygotes genotype for rs76863441, heterozygotes genotype, and wild genotype were present in 4 (6.5%), 22 (35.5%), and 36 (58.1%) of the variant angina group, respectively, and in 30 (3.4%), 246 (28.2%), and 596 (68.3%) of the control group, respectively. Statistically, there were no significant differences in genotypes between the variant angina group and the control group. Next, males and females were analyzed separately. In males, there were no significant differences in homozygous mutations (1 out of 43 patients (2.3%) in the variant angina group vs. 11 out of 327 patients (3.4%) in the control group, P=1.00). However, in females, there was a significant difference in homozygous mutations (3 out of 19 (15.8%) in the variant angina group vs. 19 out of 545 (3.4%) in the control group, P=0.033). Conclusions These findings indicate that homozygotes of rs76863441, which has PAF-AH deficiency, may be associated with the pathogenesis of variant angina in Japanese women. Further functional analyses of this mutation are of great interest.Genotypes of rs76863441Gender disparities of rs76863441

Prevalence of coronary microvascular disease in myocardial infarction with non-obstructive coronary artery disease

Abstract Background Six percent of patients presenting with acute myocardial infarction (MI) have MI with non-obstructed coronary artery disease (MINOCA). Coronary microvascular disease (CMD) is common in angina with non-obstructive coronary artery disease (ANOCA), but its prevalence and severity in MINOCA is undefined. Purpose Patients with CMD may have elevated risk of myocardial infarction despite no significant stenosis. We tested the hypothesis that patients with MINOCA have more significant burden of CMD than patients with ANOCA. Methods A retrospective case-control study was performed on patients who underwent invasive testing for signs of coronary ischemia and found to have non-obstructive disease (stenoses< 50%). Cases of MI were classified as MINOCA (n=87) and compared to patients with ANOCA (n=552). Patients with spontaneous coronary artery dissection, myocarditis, Takotsubo cardiomyopathy or prior atherothrombotic MI were excluded. Coronary catheterization was performed followed by invasive provocation testing with adenosine and acetylcholine using a Doppler flow wire. CMD was subdivided into endothelium-independent, defined as coronary flow reserve (CFR) < 2.5 with intra-coronary adenosine, and endothelium dependent, defined as < 50% increase in coronary blood flow with acetylcholine. Epicardial vasoconstriction > 90% with typical anginal symptoms was classified as epicardial vasospasm. Results There was no difference in age, sex or traditional coronary risk factors between the MINOCA and ANOCA groups (Table 1). Fifty (57%) of patients with MINOCA had type 2 MI secondary to supply-demand mismatch. Both MINOCA and suspected ANOCA patients had a high prevalence of CMD (71% vs 67%) and endothelium-independent CMD is more prevalent in MINOCA (64.5% vs 50.4%). Although odds of endothelium-dependent CMD were similar, the CFR within this group and CMD overall was worse in MINOCA patients (Figure 1). There was no difference in epicardial spasm. Conclusion Coronary microvascular disease and vasomotor dysfunction are common in patients with MINOCA, with a higher prevalence of endothelium-independent CMD and more severe CMD overall compared to patients with ANOCA. Treatment of CMD in patients with MINOCA may help reduce recurrence and warrants further investigation.

Safety and feasibility of nationwide invasive coronary function testing in patients with angina and no obstructive coronary artery disease (NL-CFT)

Abstract Background and purpose Patients with angina and no obstructive coronary artery disease (ANOCA) frequently have coronary vasomotor dysfunction (CVDys) as underlying pathophysiological mechanism, comprising epicardial spasm, microvascular spasm and/or microcirculatory dysfunction. These can be diagnosed by invasive coronary function testing (CFT), which has previously shown to be safe in tertiary and expert centres. The prevalence of CVDys and safety and feasibility of CFT is reported on in this first national collaboration network on CFT’s: NL-CFT. Methods NL-CFT is a prospective, observational registry of all consecutive patients undergoing clinically indicated CFT in 15 participating hospitals throughout the Netherlands. A complete CFT consisted of acetylcholine spasm provocation testing and assessment of microcirculatory function by either bolus thermodilution or Doppler flow velocity measurements. The prevalence of six different endotypes based on CFT results and overall safety were assessed and compared between tertiary (n=2) and non-tertiary centres (n=13). Tertiary was defined as having performed over 100 CFT’s prior to the start of NL-CFT and fulfilling a referral function with specialized ANOCA outpatient clinic. Results In total 1207 predominantly female (81%) patients with a mean age of 60±10 years were included. Traditional cardiovascular risk factors were frequently present. Almost all of the included 1207 patients underwent a complete CFT (93.4%) and prevalence of CVDys was high (77%, Fig. 1). There were 11 (0.9%) serious complications reported on, of which three were definitely related to CFT as depicted in Table 1. No procedural death, myocardial infarction or stroke was observed. Lastly, no differences were found in the occurrence of complications between tertiary an non-tertiary centres. Conclusions Coronary function testing is feasible and safe to perform nationally with a high diagnostic yield.Figure 1.Endotype distribution.Table 1.Side-effects&complication rates.

Coronary slow flow as measured by corrected TIMI frame counts is associated with impaired microvascular resistance

Abstract Background The Coronary Slow Flow Phenomenon (CSFP) reflects an increased resting microvascular resistance and has been defined as a corrected thrombolysis in myocardial infarction frame count (cTFC) >27 in the in the absence of obstructive coronary artery disease (CAD). However, there is limited and conflicting data on the diagnostic utility of CTFC with respect to gold standard coronary haemodynamic parameters; namely coronary flow reserve (CFR) and hyperaemic microvascular resistance (hMR). Purpose To evaluate the relationship between angiography-derived cTFC and the coronary haemodynamic parameters (CFR and hMR). Methods Patients with angina and non-obstructive CAD (< 50% epicardial stenosis; ANOCA) underwent comprehensive functional coronary angiography utilising a dual sensor-tipped pressure-doppler flow wire during adenosine infusion for investigation of coronary microvascular impairment, and acetylcholine provocative testing for the diagnosis of coronary artery spasm. Results In 103 patients who underwent functional coronary angiography, 60 patients had CSFP and this was associated with low flow velocity and higher microvascular resistance at rest as compared with patients without CSFP (19.2 ± 7.3 versus 22.6 ± 6.7, p=0.024; and 5.9 ± 2.0 versus 4.6 ± 1.7, p=0.009, respectively). Whilst cTFC was poorly associated with CFR (r= 0.058, p= 0.564), there was a relatively strong, positive correlation with hMR (r=0.258, p=0.008). Furthermore, receiver operating characteristic analyses demonstrated that CTFC poorly predicts an impaired CFR <2.5 (AUC, 0.479 [0.36-0.59]) but does predict an impaired hMR >2.5 (AUC, 0.623 [0.51-0.74] p=0.037). Conclusion In patients with ANOCA, cTFC is associated with coronary microvascular dysfunction as measured by microvascular resistance during hyperaemia. This data suggests the cTFC may be a surrogate marker for impaired microvascular resistance.cTFC versus hMR

Predictors of microvascular spasm by spasm provocation testing in patients having angina with no obstructive coronary arteries

Abstract Background Microvascular dysfunction in patients having angina with no obstructive coronary arteries (ANOCA) has been recognized to be associated with poor prognosis, while microvascular spasm (MVS) has not been fully studied due to its diagnostic challenge. Purpose We aimed to explore clinical and coronary physiological characteristics of MVS. Methods We retrospectively studied patients with ANOCA who underwent spasm provocation test (SPT) with intracoronary acetylcholine administration followed by coronary physiological assessment. Epicardial spasm and MVS were diagnosed in accordance with the latest guideline. Physiological indices such as coronary flow reserve (CFR), index of microcirculatory resistance (IMR) and microvascular resistance reserve (MRR) were assessed by bolus thermodilution method using pressure temperature wire in LAD and RCA. Results In a total of 141 patients, 40 (28.4%) patients were diagnosed as epicardial spasm and 22 (15.6%) were diagnosed as MVS according to the diagnostic criteria of the latest guideline. Women was more frequent (63.9% vs 27.3%, P=0.002) and IMR of LAD was significantly higher (34.80 vs 22.95, P=0.005) in patients with versus without MVS. In addition, hypertension tended to be frequent (81.8% vs 60.5%, P=0.089) in patients with MVS. In a multivariable logistic regression analysis, women (odds ratio 5.64 [OR], 95% CI 1.90 – 16.7, P=0.0018) and IMR of LAD (OR 1.02, 95% CI 1.00 – 1.05, P=0.029) were independently associated with the diagnosis of MVS. On the other hand, no clinical characteristics and physiological parameter were significantly associated with epicardial spasm. In a comparison between microvascular and epicardial spasm, women (OR 8.30, 95%CI 2.23 – 30.9, P=0.0016) and IMR of LAD (OR 1.04, 95%CI 1.00 – 1.08, P=0.0462) were still significantly more frequent in MVS patients in multivariable analysis. Conclusion Women and higher IMR of LAD were significantly frequent in patients with versus without MVS, and hypertension tended to be frequent in MVS patients.

Association of vasospastic angina with myocardial bridging and pericoronary adipose tissue attenuation on computed tomography angiography

Abstract Background Recent studies have suggested that vasospastic angina (VSA) is associated with myocardial bridging (MB). The relationship between VSA and pericoronary adipose tissue (PCAT) inflammation has also been reported but still remains to be determined. Purpose We investigated clinical and coronary computed tomography angiographic (CCTA) features in patients with VSA diagnosed by spasm provocation test (SPT). Methods We retrospectively studied patients with clinically suspected VSA who underwent both SPT with intracoronary acetylcholine administration and CCTA within three months before SPT at Tsuchiura Kyodo General Hospital. PCAT inflammation was evaluated on CCTA images by fat attenuation index (FAI) which has been recently used as a novel biomarker of coronary inflammation. In FAI analysis, we measured FAI of the proximal segments not only for 4mm (FAI4mm) but also for the inner and thinner 2mm pericoronary adipose tissue layer from the vessel wall (FAI2mm), since FAI2mm has been reported to provide better discriminating efficacy for VSA diagnosis than FAI4mm. We also evaluated the presence or absence of MB and its features including length, depth and location on CCTA images. Results A total of 172 patients were studied and VSA was diagnosed in 39.0% (67/172) of patients by SPT according to the latest guideline. Male (74.6% vs 49.5%, P=0.001), smoking history (74.6% vs 48.6%, P=0.001) were more frequent, and prevalence of CCTA-defined MB (47.8% vs 34.3%, P=0.082) and RCA-FAI2mm (-68.73 HU vs -73.35 HU, P<0.001) were higher in patients with versus without VSA. In multivariable analysis, presence of CCTA-defined MB (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.26-5.19, P=0.0095), RCA-FAI2mm (OR 1.05, 95% CI 1.01-1.09, P=0.025), and smoking (OR 3.40, 95% CI 1.57-7.36, P=0.0019) were independently associated with VSA. A combination of high RCA-FAI2mm (≥-68.93HU, the best cut-off obtained by ROC analysis with AUC of 0.64, 95% CI 0.551 - 0.728), smoking history and existence of MB could predict VSA with 73.7% of probability, while an absence of all 3 covariates could exclude VSA with 85.3% of probability. Conclusion CCTA-defined MB, high RCA-FAI2mm and smoking were independently predictive of VSA.