Association of the interleukine-6 polymorphism with catheter-induced coronary artery spasm in Egyptians.

BACKGROUND: The role of coronary artery spasm (CAS) was extended beyond variant angina to ischemic heart disease in general, including effort angina, unstable angina, acute myocardial infarction (MI) and sudden death. It is difficult and cumbersome to examine CAS during coronary angiography. Risk factors for CAS include smoking and genetic polymorphisms. AIM: We aimed to investigate the association of the interleukin-6 (IL-6) polymorphism with catheter-induced CAS in Egyptian patients who undergo coronary angiography. METHODS: This is a case-control study. Two hundred patients with chronic coronary artery disease who underwent elective coronary angiography were included in the study. Patients were divided into two groups: the non-CAS group (100 patients) and the CAS group (100 patients). The subjects were genotyped to the -572 C>G (rs 1800796) polymorphism of the IL-6 gene by PCR-restriction fragment length polymorphism. RESULTS: We found that patients with CAS have more risk factors for atherosclerosis compared to those without CAS. Smoking, the IL-6 GG genotype, and the G allele were independent risk factors for CAS. CONCLUSION: We concluded that the GG genotype and G allele of the IL-6 gene are associated with CAS. Smoking, the GG genotype, and the G allele of the IL-6 gene are independent predictors of catheter-induced CAS.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing.

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Long-term prognostic factors for cardiovascular events in patients with chest pain without diabetes mellitus nor significant coronary stenosis.

Chest pain is the most common symptom of coronary artery disease (CAD) and diabetes mellitus (DM) is a well-known single strongest risk factor for cardiovascular diseases. Thus, the impact of CAD nor DM on long-term clinical effects is reported widely, but the prognostic factors of non-DM patients presenting with chest pain without significant CAD are limited. A total of 1,046 patients with chest pain without DM and significant CAD who underwent coronary angiography (CAG) and acetylcholine (ACH) provocation tests were finally enrolled. Propensity score matching and multivariate Cox-proportional hazard ratio analysis were performed to adjust for baseline potential confounders. Major adverse cardiac and cerebrovascular events (MACCE) were defined as the composite of total death, myocardial infarction (MI), revascularization, stroke, and recurrent angina. This study aimed to evaluate the long-term prognostic factors for MACCE in patients with chest pain without DM and CAD up to 5 years. Coronary artery spasm (CAS) was the most common cause of chest pain. However, long-term MACCE of CAS was not worse than those of patients with chest pain without CAS when patients with CAS had subsequent optimal antianginal medication therapy. However, a recurrent chest pain remains a problem even with continuous antianginal medication therapy. Up to 5 years, the incidence of MACCE was in 7.3%, including recurrent angina 6.9%. Dyslipidemia (HR: 2.010, 95% CI 1.166-3.466, P = 0.012), mild-moderate (30-70%) coronary stenosis (HR: 2.369, 95% CI 1.118-5.018, P = 0.024), the use of aspirin (HR: 2.885, 95% CI 1.588-5.238, P < 0.001), and the use of nitrates (HR: 1.938, 95% CI 1.094-3.433, P = 0.023) were independent risk factors for MACCE. Among the patients with chest pain without DM and significant CAD, the incidence of MACE were rare, but recurrent angina was still a challenging problem who had treated with antianginal medications.

Comparison of clinical outcomes in patients with mixed angina and pure vasospastic angina.

OBJECTIVE: This study investigated differences in clinical outcomes between mixed angina (MA) and pure vasospastic angina (PVA). METHODS: A total of 524 vasospastic angina patients who did or did not have >50% coronary artery stenosis from January 2005 to January 2021 were divided into two groups (Group 1: PVA, N  = 399; Group 2: MA, N  = 125) and then three groups [Group 1: PVA, N  = 399; Group 2: MA without percutaneous coronary intervention (PCI), N  = 67; Group 3: MA with PCI, N  = 58] for assessment. We recorded the incidence of major adverse cardiac and cerebrovascular events (MACCE: the composite of death, myocardial infarction, nonfatal stroke or rehospitalization) during 3-year clinical follow-up. RESULTS: Compared to the PVA group, there were significant differences in MACCE (20.8% vs. 11.8%, P  = 0.011) and rehospitalization (20.0% vs. 9.8%, P  = 0.002) in the MA group. Kaplan-Meier analysis showed that patients in the MA with PCI group had the highest cumulative incidence rate of MACCE during the 3-year follow-up (log-rank P  < 0.001). CONCLUSION: Compared with the PVA patients, MA patients had significantly worse clinical outcomes during long-term follow-up.

Familial risk of vasospastic angina: a nationwide family study in Sweden.

OBJECTIVES: Vasospastic angina (VSA) is a complex coronary vasomotor disorder associated with an increased risk of myocardial infarction and sudden death. Despite considerable advances in understanding VSA pathophysiology, the interplay between genetic and environmental factors remains elusive. Accordingly, we aimed to determine the familial VSA risk among first-degree relatives of affected individuals. METHODS: A population-based multigenerational cohort study was conducted, including full-sibling pairs born to Swedish parents between 1932 and 2018. Register-based diagnoses were ascertained through linkage to the Swedish Multigeneration Register and National Patient Register. Incidence rate ratios (IRRs) and adjusted HRs were calculated for relatives of individuals with VSA compared with relatives of individuals without VSA. RESULTS: The total study population included 5 764 770 individuals. Overall, 3461 (0.06%) individuals (median age at disease onset 59 years, IQR: 63-76) were diagnosed with VSA. Of these, 2236 (64.61%) were women. The incidence rate of VSA for individuals with an affected sibling was 0.31 (95% CI: 0.24 to 0.42) per 1000 person-years compared with 0.04 (95% CI: 0.04 to 0.04) per 1000 person-years for those without an affected sibling, yielding an IRR of 7.58 (95% CI: 5.71 to 10.07). The risk of VSA for siblings with an affected sibling was significantly increased in the fully adjusted model (HR: 2.56; 95% CI: 1.73 to 3.79). No increased risk of VSA was observed in spouses of affected individuals (HR: 0.63; 95% CI: 0.19 to 2.09). CONCLUSIONS: In this nationwide family study, we identified high familial risk for VSA independent of shared environmental risk factors. Our findings indicate that VSA tends to cluster in families, emphasising the need to explore genetic and non-genetic factors that may contribute.

Effect of Statins on Major Adverse Cardiovascular Events in Patients with Coronary Artery Spasm: A Meta-Analysis of the Asia Region.

Background: Whether statins can reduce major cardiovascular adverse events (MACE) in patients with coronary artery spasm (CAS) is controversial. And most of the relevant research to date has been conducted in Asia. Methods: We systematically searched electronic databases for studies on the effect of statins on MACE in patients with CAS in Asia and published up to September 2022. We included data on MACE in a statin therapy patient group and a no-statin therapy control group. We then evaluated the effect of statin therapy on MACE in patients with CAS in Asia by meta-analysis and trial sequential analysis (TSA). All statistical analyses were performed using Stata 16.0 software and TSA software. Results: A total of 10 studies (n = 9333 patients) were included in the final analysis. Meta-analysis showed that the use of statins had a significant effect on MACE in CAS patients (with RR, 0.70; 95% CI, 0.49-0.99), and the sensitivity analysis further confirmed this finding. Subgroup analysis suggested that the correlation between statin therapy and reduced MACE endpoint was stronger in Japanese patients and patients followed up for more than 4 years. But our TSA results indicated that the available samples were insufficient and further research is needed. Conclusions: Our meta-analysis suggests that statin therapy can reduce MACE in patients with CAS in Asia, and the correlation between the two was stronger in Japanese patients and patients followed up for more than 4 years.

Relationship between Inflammation and Vasospastic Angina.

Coronary artery spasm (CAS) is a dynamic coronary stenosis causing vasospastic angina (VSA). However, VSA is a potentially lethal medical condition with multiple presentations, including sudden cardiac death. Despite investigations to explore its pathogenesis, no single mechanism has been found to explain the entire process of VSA occurrence. The roles of elevated local and systemic inflammation have been increasingly recognized in VSA. Treatment strategies to decrease local and systemic inflammation deserve further investigation.

Sex-related differences in coronary vasomotor disorders: Comparisons between Western and Japanese populations.

Sex-related differences in the prevalence of cardiac disorders have been elucidated beyond races. Angina/ischemia with nonobstructive coronary artery disease (AINOCA) is often observed in females. Coronary microvascular dysfunction (CMD) and coronary epicardial spasm (CES) are the principal cause of AINOCA. The clinical outcomes of Western patients with CMD were less satisfactory than expected, while the prognosis of Japanese patients with CES treated with medications including calcium channel blockers was favorable. However, the incidence and clinical features of coronary spasm endotypes were different between Western and Japanese populations. Furthermore, sex-related differences in the clinical manifestations and outcomes of patients with different spasm endotypes remain uncertain beyond race. In this article, we will review the sex differences in Japanese AINOCA patients with coronary vasomotor disorders, including CMD and CES, and compare them with those of Western patients.

Sex Difference in Coronary Artery Spasm Tested by Intracoronary Acetylcholine Provocation Test in Patients with Nonobstructive Coronary Artery Disease.

Introduction: Cardiovascular diseases manifest differently in men and women. The purpose of this study is to compare the sex difference in the characteristics of coronary artery spasm (CAS) in patients with nonobstructive cardiovascular disease (NOCVD) and the clinical outcomes in accordance with sex in CAS patients. Methods: The study analysed 5,491 patients with NOCVD who underwent an acetylcholine provocation test from November 2004 to May 2014 for evaluation of chest pain. CAS was defined as greater than 70% of luminal narrowing of the artery during the acetylcholine provocation test. Results: The patients were divided into men (n = 2,506) and women (n = 2,985). Mean follow-up days were 1,218 ± 577 days. To adjust for confounding factors, the propensity score matching (PSM) analysis was performed in all patients and among the CAS patients. After PSM analysis, a total of 1,201 pairs in all patients and a total of 713 pairs in CAS patients were generated. In all patients, women showed significantly less incidence of CAS compared with men (62.3% vs 50.9%, P < 0.01). Myocardial bridge (MB) and moderate stenosis were less prevalent in women, while transient ST elevation and ischemic chest pain during provocation were more frequent in women. In CAS patients, men had a higher incidence of multivessel spasm than women (35.7% vs. 29.7%, P < 0.01). Old age, dyslipidemia, and MB were independent risk factors of CAS in both men and women. In CAS patients, there was no statistical differences for various individual and composite major outcomes up to five years in either men or women. In men with CAS, old age was a risk factor of a 5-year major adverse cardiac event (MACE), and moderate stenosis was a risk factor of both 5-year MACE and 5-year recurrent angina. In women with CAS, mild stenosis was a risk factor of 5-year MACE, while myocardial bridge was a risk factor of 5-year recurrent angina. Conclusions: In this study, there were sex differences in the angiographic and clinical parameters during the acetylcholine provocation test, incidence of CAS, risk factors of CAS, 5-year MACE, and recurrent angina. Old age, dyslipidemia, and MB were independent risk factors of CAS in both sexes. However, major clinical outcomes up to five years in CAS patients were not different according to sex.

Impact of statins in patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood. METHODS: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors. RESULTS: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98). CONCLUSION: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients.

Impact of drug-eluting stent-associated coronary artery spasm on 3-year clinical outcomes: A propensity score matching analysis.

BACKGROUND: It has been reported that significant endothelial dysfunction or clinically evident vasospasm can be associated with drug-eluting stents (DESs). However, the impact of DES associated coronary artery spasm (CAS) on long-term clinical outcomes has not been fully elucidated as compared with those of patients with vasospastic angina. METHODS: A total of 2797 consecutive patients without significant coronary artery lesion (<70%), who underwent the Acetylcholine (Ach) provocation test, were enrolled between Nov 2004 and Oct 2010. DES-associated spasm was defined as significant CAS in proximal or distal to previously implanted DES site at follow-up angiography with Ach test. Patients were divided into two groups (DES-CAS; n = 108, CAS; n = 1878). For adjustment, propensity score matching (PSM) was done (C-statistics = 0.766, DES-CAS; n = 102, CAS; n = 102). SPSS 20 (Inc., Chicago, Illinois) was used to analyze this data. RESULTS: Baseline characteristics were worse in the DES-CAS group. After PSM, both baseline characteristics and the Ach test results were balanced except higher incidence of diffuse CAS and ECG change in the DES-CAS group. During Ach test, the incidence of diffuse spasm (93.1% vs. 81.3%, p = 0.012) and ST-T change (10.7% vs. 1.9%, p = 0.010) were higher in the DES-CAS group. At 3-year, before and after adjustment, the DES-CAS group showed a higher incidence of coronary revascularization (9.8% vs. 0.0%, p = 0.001), recurrent chest pain requiring follow up coronary angiography (CAG, 24.5% vs. 7.8%, p = 0.001) and major adverse cardiac events (MACEs, 9.8% vs. 0.9%, p < 0.005). CONCLUSION: In this study, DES associated CAS was associated with higher incidence of diffuse spasm, ST-T change and adverse 3-year clinical outcomes. Special caution should be exercised in this particular subset of patients.

Percutaneous coronary intervention in patients with documented coronary vasospasm during long-term follow-up.

OBJECTIVE: Although recurring coronary artery spasm (CAS) may lead to the development of fixed atherosclerotic coronary stenosis (FS), the relationship between coronary atherosclerosis and CAS is still speculative. We evaluated the incidence of FS requiring percutaneous coronary intervention (PCI) in patients with documented CAS during long-term follow-up and analysed their clinical features. METHODS: Clinical data of 3556 patients during a median follow-up of 9.4 years after non-invasive ergonovine spasm provocation testing with echocardiographic monitoring of left ventricular wall motion (erg echo) were analysed. RESULTS: Erg echo documented CAS in 830 (23.3%) patients, who had higher frequencies of coronary risk factors than those without CAS. Patients with documented CAS on erg echo showed significantly lower 10-year overall (90.5% vs 94.2%, p<0.001) and PCI-free (97.4% vs 98.4%, p=0.002) survival rates than those without CAS. Documented CAS was an independent factor associated with later PCI after adjustment by either Cox regression model or Fine-Gray competing risk model. There was no significant difference in baseline clinical characteristics between patients who needed later PCI and those who did not. Among 28 patients who needed later PCI after documentation of CAS, the original CAS and later PCI territory were concordant in 25 (89.3%), while 3 (10.7%) showed discordance. CONCLUSIONS: CAS is a risk factor for the development of FS requiring PCI during long-term follow-up, and warrants physicians' vigilance and careful follow-up of patients with documented CAS and insignificant stenosis of major epicardial coronary arteries at the time of initial diagnosis.

Prevalence of Coronary Microvascular Disease and Coronary Vasospasm in Patients With Nonobstructive Coronary Artery Disease: Systematic Review and Meta-Analysis.

Background A relevant proportion of patients with suspected coronary artery disease undergo invasive coronary angiography showing normal or nonobstructive coronary arteries. However, the prevalence of coronary microvascular disease (CMD) and coronary spasm in patients with nonobstructive coronary artery disease remains to be determined. The objective of this study was to determine the prevalence of coronary CMD and coronary vasospastic angina in patients with no obstructive coronary artery disease. Methods and Results A systematic review and meta-analysis of studies assessing the prevalence of CMD and vasospastic angina in patients with no obstructive coronary artery disease was performed. Random-effects models were used to determine the prevalence of these 2 disease entities. Fifty-six studies comprising 14 427 patients were included. The pooled prevalence of CMD was 0.41 (95% CI, 0.36-0.47), epicardial vasospasm 0.40 (95% CI, 0.34-0.46) and microvascular spasm 24% (95% CI, 0.21-0.28). The prevalence of combined CMD and vasospastic angina was 0.23 (95% CI, 0.17-0.31). Female patients had a higher risk of presenting with CMD compared with male patients (risk ratio, 1.45 [95% CI, 1.11-1.90]). CMD prevalence was similar when assessed using noninvasive or invasive diagnostic methods. Conclusions In patients with no obstructive coronary artery disease, approximately half of the cases were reported to have CMD and/or coronary spasm. CMD was more prevalent among female patients. Greater awareness among physicians of ischemia with no obstructive coronary arteries is urgently needed for accurate diagnosis and patient-tailored management.

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

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

Gender differences in factors associated with vasospastic angina.

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

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

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

Association between Coronary Artery Spasm and the risk of incident Diabetes: A Nationwide population-based Cohort Study.

Background: Non-diabetic coronary artery spasm (CAS) without obstructive coronary artery disease increases insulin resistance. We investigated the risk of incident type 2 diabetes (diabetes) associated with CAS. Methods: Patient records were retrospectively collected from the Taiwan National Health Insurance Research Database during the period 2000-2012. The matched cohorts consisted of 12,413 patients with CAS and 94,721 patients in the control group. Results: During the entire follow-up, the incidence of newly-diagnosed diabetes was 22.2 events per 1000 person-years in the CAS group and 13.9 events per 1000 person-years in the control group. The increased risk of CAS-related incident diabetes was observed regardless of sex and length of follow-up. The median time to incident diabetes was 2.9 and 3.5 years in the CAS and the control group (P <0.001), respectively, regardless of sex. Although age did not affect the risk of CAS-related incident diabetes, the risk was less apparent in the subgroups of male, dyslipidemia, chronic obstructive pulmonary disease, stroke, gout and medicated hypertension. However, CAS patients aged <50 years compared with patients ≥50 years had a greater risk of incident diabetes in females but not in males. Older CAS patients developed diabetes in a shorter length of time than younger patients. Conclusion: CAS is a risk factor for incident diabetes regardless of sex. However, females aged <50 years have a more apparent risk for CAS-related diabetes than old females, which is not observed in males. The median time of 2.9 years to incident diabetes warrants close follow-up.

Vasomotor dysfunction in patients with angina and nonobstructive coronary artery disease is dominated by vasospasm.

BACKGROUND: Coronary vasomotor dysfunction, comprising endotypes of coronary spasm and/or impaired microvascular dilatation (IMD), is common in patients with angina and no obstructive coronary arteries (ANOCA). However, there are discrepant reports regarding the prevalence of these endotypes. The objective of this study was to determine the prevalence of coronary vasomotor dysfunction in patients with ANOCA, underlying endotypes, and differences in clinical characteristics. METHODS: Prospective registry of patients with ANOCA that underwent clinically indicated invasive coronary function testing (CFT), including acetylcholine spasm testing (2-200 µg) to diagnose coronary spasm, and adenosine testing (140 µg/kg/min) to diagnose IMD, defined as an index of microvascular resistance ≥25 and/or coronary flow reserve <2.0. RESULTS: Of the 111 patients that completed CFT (88% female, mean age 54 years), 96 (86%) showed vasomotor dysfunction. The majority 93 (97%) had coronary spasm, 63% isolated and 34% combined with IMD. Isolated IMD was rare, occurring in only 3 patients (3%). Hypertension was more prevalent in patients with vasomotor dysfunction compared to those without (39% vs. 7%, p = 0.02). Obesity and a higher severity of angiographic atherosclerotic disease were more prevalent in patients with coronary spasm compared to those without (61% vs. 28%; 40% vs. 0%, respectively, both p < 0.01). No differences in angina characteristics were observed between patients with and without vasomotor dysfunction or between endotypes. CONCLUSIONS: Coronary vasomotor dysfunction is highly prevalent in patients with ANOCA, especially epicardial or microvascular vasospasm, whereas isolated IMD was rare. Performing a CFT without acetylcholine testing should be strongly discouraged.

Sex-related Differences in Patients with Positive Coronary Spasm as Identified by Acetylcholine Testing.

Objective A pathological acetylcholine (ACh) test was observed at lower ACh doses in females compared with males in European populations. We retrospectively analyzed the sex-related differences in Japanese patients with provoked positive spasm by ACh spasm provocation testing. Methods We performed the ACh spasm provocation tests in 1,854 patients from Jan 1991 until Mar 2019. 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 spasm was defined as >90% stenosis and usual chest pain or ischemic ECG changes. We compared the clinical characteristics, angiographical findings during ACh testing, and clinical outcomes between female and male patients with and without provoked positive spasm. Results Positive provoked spasm was diagnosed in 917 patients including 737 (80.4%) males and 180 (19.6%) females. The incidence of provoked positive spasm in females was significantly lower than that in males (33.5% vs. 56.0%, p<0.001). Female patients with provoked positive spasm tended to be older, have less history of smoking, less provoked spasm in the left circumflex artery, or less focal type spasm than male patients with provoked positive spasm. The incidence of ST elevation during ACh testing in male patients was significantly higher than that in female patients, whereas the frequency of ST depression in females was remarkably higher than that in males. The mean maximum used ACh dose for provoked positive spasm on both coronary arteries in female patients was significantly higher than that in male patients. The observed major complications during ACh testing did not differ substantially between the sexes. In addition, the prognosis in females with provoked positive spasm was not different from males. Conclusion Provoked positive spasm by ACh test was obtained at lower mean maximum ACh doses in males compared with females in Japanese patients.

Incidence and Characteristics of Coronary Artery Spasms Related to Atrial Fibrillation Ablation Procedures　- Large-Scale Multicenter Analysis.

BACKGROUND: Coronary artery spasms (CASs), which can cause angina attacks and sudden death, have been recently reported during catheter ablation. The aim of the present study was to report the incidence, characteristics, and prognosis of CASs related to atrial fibrillation (AF) ablation procedures.Methods and Results:The AF ablation records of 22,232 patients treated in 15 Japanese hospitals were reviewed. CASs associated with AF ablation occurred in 42 of 22,232 patients (0.19%). CASs occurred during ablation energy applications in 21 patients (50%). CASs also occurred before ablation in 9 patients (21%) and after ablation in 12 patients (29%). The initial change in the electrocardiogram was ST-segment elevation in the inferior leads in 33 patients (79%). Emergency coronary angiography revealed coronary artery stenosis and occlusions, which were relieved by nitrate administration. No air bubbles were observed. A comparison of the incidence of CASs during pulmonary vein isolation between the different ablation energy sources revealed a significantly higher incidence with cryoballoon ablation (11/3,288; 0.34%) than with radiofrequency catheter, hot balloon, or laser balloon ablation (8/18,596 [0.04%], 0/237 [0%], and 0/111 [0%], respectively; P<0.001). CASs most often occurred during ablation of the left superior pulmonary vein. All patients recovered without sequelae. CONCLUSIONS: CASs related to AF ablation are rare, but should be considered as a dangerous complication that can occur anytime during the periprocedural period.