Protocol Variation in Functional Coronary Angiography Among Patients With Suspected Angina With Non-Obstructive Coronary Arteries: A Nationwide Snapshot of Current Practice Within Australia and New Zealand.

BACKGROUND: Functional coronary angiography (FCA) for endotype characterisation (vasospastic angina [VSA], coronary microvascular disease [CMD], or mixed) is recommended among patients with angina with non-obstructive coronary arteries. Whilst clear diagnostic criteria for VSA and CMD exist, there is no standardised FCA protocol. Variations in testing protocol may limit the widespread uptake of testing, generalisability of results, and expansion of collaborative research. At present, there are no data describing protocol variation across an entire geographic region. Therefore, we aimed to capture current practice variations in the approach to FCA to improve access and standardisation for diagnosis of coronary vasomotor disorders in Australia and New Zealand. METHOD: Between July 2022 and July 2023, we conducted a national survey across all centres in Australia and New Zealand with an active FCA program. The survey captured attitudes towards FCA and protocols used for diagnosis of coronary vasomotor disorders at 33 hospitals across Australia and New Zealand. RESULTS: Survey responses were received from 39 clinicians from 33 centres, with representation from centres within all Australian states and territories and both North and South Islands of New Zealand. A total of 21 centres were identified as having an active FCA program. In general, respondents agreed that comprehensive physiology testing helped inform clinical management. Barriers to program expansion included cost, additional catheter laboratory time, and the absence of an agreed-upon national protocol. Across the clinical sites, there were significant variations in testing protocol, including the technique used (Doppler vs thermodilution), order of testing (hyperaemia resistance indices first vs vasomotor function testing first), rate and dose of acetylcholine administration, routine use of temporary pacing wire, and routine single vs multivessel testing. Overall, testing was performed relatively infrequently, with very little follow-on FCA performed, despite nearly all respondents believing this would be clinically useful. CONCLUSIONS: This survey demonstrates, for the first time, variations in FCA protocol among testing centres across two entire countries. Furthermore, whilst FCA was deemed clinically important, testing was performed relatively infrequently with little or no follow-on testing. Development and adoption of a standardised national FCA protocol may help improve patient access to testing and facilitate further collaborative research within Australia and New Zealand.

Visual Estimates of Coronary Slow Flow Are Not Associated With Invasive Wire-Based Diagnoses of Coronary Microvascular Dysfunction.

BACKGROUND: Coronary slow flow (CSF) by invasive coronary angiography is frequently understood to be an indicator of coronary microvascular dysfunction (CMD) in patients with ischemia with nonobstructive coronary arteries. However, the relationship between visual estimates of CSF and quantitative wire-based invasive diagnosis of CMD is uncertain. METHODS: We prospectively enrolled adults aged ≥18 years with stable ischemic heart disease who were referred for invasive coronary angiography. Individuals with ≥50% epicardial coronary artery stenosis were excluded. Invasive coronary angiography was reviewed for CSF, defined as ≥3 cardiac cycles to opacify distal vessels with contrast. Coronary function testing was performed in the left anterior descending coronary artery using bolus coronary thermodilution techniques to measure coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR). Invasively determined CMD was defined as abnormal CFR (<2.5), abnormal IMR (≥25), or both. RESULTS: Among 104 participants, the median age was 61.5 years and 79% were female. The median CFR was 3.6 (interquartile range, 2.5-4.7) and the median IMR was 21 (interquartile range, 13.3-28.0). Overall, 24.0% of participants had abnormal CFR, 34.6% had abnormal IMR, and 48.1% had a final diagnosis of invasively determined CMD. CSF was present in 23 participants (22.1%). The proportions of patients with CMD (56.5% versus 45.7%; P=0.36), abnormal CFR (17.4% versus 25.9%; P=0.40), and abnormal IMR (43.5% versus 32.1%; P=0.31) were not different in patients with versus without CSF. CONCLUSIONS: Among patients with ischemia with nonobstructive coronary artery, CSF was not associated with abnormal CFR, IMR, or either abnormal CFR or IMR. CSF is not a reliable angiographic surrogate of abnormal CFR or IMR as determined by invasive, wire-based physiology testing. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03537586.

Microvascular vasoregulatory dysfunction in African Americans - An enhanced opportunity for early prevention and treatment of atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease and its risk factors and precursors are a major driver of disparities in cardiovascular health. This review examines reported evidence that vascular endothelial dysfunction, and its manifestation as coronary microvascular dysfunction, underlies observed excess morbidity and mortality in African Americans. Advanced imaging insights that reveal patho-mechanisms, along with population evidence from the Jackson Heart Study, and the growing evidence emanating from national and international clinical trials and registries are presented. We examine a physiological framework that recognizes insulin-resistant cardiometabolic underpinnings of the conditions of the American Heart Associations' Life's Essential Eight construct of cardiovascular health as a unifying basis that affords early prevention. Mechanistic-based therapeutic approaches, can subsequently be implemented to interrupt progression to adverse outcomes employing layered, or personalized, treatment strategies of a well-defined set of conditions or diseases. Remaining knowledge gaps are acknowledged.

Angiographic Coronary Slow Flow Is Not a Valid Surrogate for Invasively Diagnosed Coronary Microvascular Dysfunction.

BACKGROUND: Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain. OBJECTIVES: The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD. METHODS: Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent. RESULTS: Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80). CONCLUSIONS: Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD.

The invasive investigation of INOCA in the coronary catheterization lab.

Over half of all patients with angina have no angiographically demonstratable obstructive coronary disease, with a significant proportion of these patients having undiagnosed microvascular dysfunction and/or vasospastic angina. In chronic coronary syndrome, ischemia with non-obstructive coronary artery disease (INOCA) often remains undiagnosed, or uninvestigated. INOCAmay occur due to vasospastic angina and microvascular dysfunction and require invasive assessment in the coronary catheterization lab. To evaluate INOCA coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) are used to assess microvascular dysfunction before acetylcholine provocation testing for coronary spasm. This review provides an overview of the invasive investigation of INOCA in the coronary catheterization lab for patients with angina to be optimally managed.

Ischemic Myocardial Positron Emission Tomography Perfusion Without Epicardial Coronary Disease in Hypertrophic Obstructive Cardiomyopathy.

The presence of impaired microvascular coronary flow (MCF) identified by positron emission tomography myocardial perfusion imaging (PET-MPI) has been described in hypertrophic obstructive cardiomyopathy (HOCM) patients, contributes to blunted myocardial perfusion during vasodilator stress, and is a strong predictor of poor prognosis. A 45-year-old female with hypertension and obesity presented with angina. Her PET-MPI displayed vasodilator stress-induced global LV ischemia. However, her coronary angiogram revealed no obstructive coronary disease. These contradictory findings triggered a more thorough cardiac MRI with diffuse myocardial fibrosis, indicating high-risk HOCM. She underwent implantable cardioverter-defibrillator (ICD) placement due to non-sustained ventricular tachycardia and syncope. While this patient lacked epicardial coronary disease, her PET-MPI demonstrated global LV ischemia due to decreased MCF, leading to inadequate augmentation of myocardial perfusion during hyperemia. This is a well-described phenomenon responsible for anginal symptoms in HOCM patients. HOCM hearts have abnormally thick coronary arterioles and decreased capillary density, leading to increased oxygen diffusion distances and reduced perfusion. The presence of vasodilator-induced, global ischemia on PET-MPI without epicardial stenosis should raise suspicion for HOCM with impaired MCF, which represents a high-risk population with an almost 10 times greater risk of cardiovascular mortality compared to hypertrophic cardiomyopathy with preserved MCF.

Living with myocardial ischaemia and no obstructive coronary arteries: a qualitative study.

OBJECTIVE: To explore the lived experience of people with myocardial ischaemia with no obstructive arteries. DESIGN: Qualitative study using semistructured interviews. SETTING: Telephone interviews with 17 participants living in the UK. PARTICIPANTS: 17 people (2 males, 15 females; aged 31-69 years) with a presumed or confirmed diagnosis of myocardial ischaemia with no obstructive arteries, recruited via social media and online patient-led support forums. RESULTS: Five themes were generated. Theme 1 describes the wide range of experiences that participants described, particularly the frequency and intensity of symptoms, and the uncertainty and fear that symptoms commonly provoked. Theme 2 describes the major impact on social relationships, employment and other aspects of everyday life. Theme 3 illustrates challenging and traumatising experiences participants described around pathways to diagnosis and accessing medical support. Theme 4 highlights the lack of consensus and clarity that participants had been confronted with around treatment and management. Theme 5 describes coping and supportive strategies valued by participants. CONCLUSIONS: This study provides insight into the challenges of living with myocardial ischaemia with no obstructive arteries. Findings highlight the significant psychological impact on people living with these conditions and the need for improvements in diagnosis, support and long-term management.

"The INOCA-IT: Rationale and design of a multicenter registry investigating ischemia in patients with non-obstructive coronary artery (INOCA) disease in Italy".

BACKGROUND: Ischemia with non-obstructive coronary artery (INOCA) disease is being progressively acknowledged as one of the pathophysiological mechanisms of chronic coronary syndrome (CCS) in an increasingly wide range of clinical pictures. Although the research has already begun to move towards a defined diagnostic pathway and a specific medical therapy for this disease, at present it remains a clinical challenge, especially if not thoroughly investigated. METHODS AND RESULTS: The INOCA IT Multicenter Registry RF-2019-12369486 is a prospective, multicentric, non-randomized, single-arm, open label clinical study which aims to evaluate the efficacy of a stratified diagnostic and therapeutic approach on adverse events prevention and symptom relief in Italian patients with INOCA disease. The study population includes patients with a clinical presentation of CCS for angina and/or positive stress test for myocardial ischemia and evidence of non-obstructive coronary artery disease (CAD) at coronary angiography. In these patients a complete invasive coronary physiology assessment is performed with the guidewire-based measurement of coronary flow reserve (CFR) and index of microvascular resistance (IMR), followed by acetylcholine (ACh) spasm provocation test. On the basis of the results of coronary function testing, patients are stratified into different INOCA endotypes (coronary microvascular disease, vasospastic angina, microvascular spasm, non-cardiac chest pain) and given a tailored medical therapy in accordance with the latest scientific evidence. At one year follow-up the impact of such a target therapy on angina class and quality of life, as well as on cardiovascular adverse events (hospitalization and coronary revascularization) is evaluated. CONCLUSIONS: The INOCA-IT Multicenter Registry will inform clinicians on sex-specific prevalence of INOCA in Italy and will show the impact of a stratified diagnostic and therapeutic approach on symptoms burden and prognosis of INOCA patients.

Efficacy of Angiotensin-Converting Enzyme Inhibitors in Coronary Microvascular Dysfunction: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Coronary microvascular dysfunction (CMD) is becoming increasingly recognized as an important contributor to the development of ischemic heart diseases. Without obstructive coronary artery disease, the physiological function of the coronary microcirculation can be altered by structural, functional, and molecular factors, leading to myocardial ischemia. CMD can significantly impact the quality of life and prognosis and imposes a huge financial burden on healthcare systems and people. This meta-analysis aims to investigate the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for treating CMD. A systematic literature review identified randomized controlled trials (RCTs) comparing ACEIs with placebo in CMD patients. Review Manager, 5.3 for Windows, was utilized. Using the Mantel-Haenszel (M-H) method, improvement in coronary flow reserve (CFR) and systolic blood pressure events was pooled as mean difference (MD) in a meta-analysis model with a fixed effect model, whereas the number of chest pain episodes was pooled as MD with a random effect model. Five randomized controlled trials involving 209 patients were included in the analysis. The analysis demonstrated a statistically significant improvement in CFR in the ACEIs group compared to the placebo group (MD -0.3, 95% CI -0.61 to 0.01, P = 0.05). However, there was no significant difference in the number of chest pain episodes between the ACEIs and placebo groups (MD 1.79, 95% CI -3.99 to 7.58, P = 0.54). Similarly, no significant difference in blood pressure change was observed between the two groups (MD 4.02, 95% CI -3.25 to 11.28, P = 0.28). In conclusion, the appropriate treatment for CMD is a source of contention because adequate data is lacking. Our findings suggest that ACEIs may have a positive effect on improving CFR in patients with microvascular angina. However, ACEIs did not demonstrate a significant impact on the number of chest pain episodes or systolic blood pressure in this patient population. Further research, including RCTs with larger sample sizes and longer follow-up durations, is warranted to provide more conclusive evidence on the role of ACEIs in CMD management.

Ischemia but no obstructive coronary artery disease: more than meets the eye.

Symptomatic women with angina are more likely to have ischemia with no obstructive coronary arteries (INOCA) compared to men. In both men and women, the finding of INOCA is not benign and is associated with adverse cardiovascular events, including myocardial infarction, heart failure and angina hospitalizations. Women with INOCA have more angina and a lower quality of life compared to men, but they are often falsely reassured because of a lack of obstructive coronary artery disease (CAD) and a perception of low risk. Coronary microvascular dysfunction (CMD) is a key pathophysiologic contributor to INOCA, and non-invasive imaging methods are used to detect impaired microvascular flow. Coronary vasospasm is another mechanism of INOCA, and can co-exist with CMD, but usually requires invasive coronary function testing (CFT) with provocation testing for a definitive diagnosis. In addition to traditional heart disease risk factors, inflammatory, hormonal and psychological risk factors that impact microvascular tone are implicated in INOCA. Treatment of risk factors and use of anti-atherosclerotic and anti-anginal medications offer benefit. Increasing awareness and early referral to specialized centers that focus on INOCA management can improve patient-oriented outcomes. However, large, randomized treatment trials to investigate the impact on major adverse cardiovascular events (MACE) are needed. In this focused review, we discuss the prevalence, pathophysiology, presentation, diagnosis and treatment of INOCA.

Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial.

BACKGROUND: We investigated the usefulness of invasive coronary function testing to diagnose the cause of angina in patients with no obstructive coronary arteries. METHODS: Outpatients referred for coronary computed tomography angiography in 3 hospitals in the United Kingdom were prospectively screened. After coronary computed tomography angiography, patients with unobstructed coronary arteries, and who consented, underwent invasive endotyping. The diagnostic assessments included coronary angiography, fractional flow reserve (patient excluded if ≤0.80), and, for those without obstructive coronary artery disease, coronary flow reserve (abnormal <2.0), index of microvascular resistance (abnormal ≥25), and intracoronary infusion of acetylcholine (0.182, 1.82, and 18.2 µg/mL; 2 mL/min for 2 minutes) to assess for microvascular and coronary spasm. Participants were randomly assigned to disclosure of the results of the coronary function tests to the invasive cardiologist (intervention group) or nondisclosure (control group, blinded). In the control group, a diagnosis of vasomotor angina was based on medical history, noninvasive tests, and coronary angiography. The primary outcome was the between-group difference in the reclassification rate of the initial diagnosis on the basis of coronary computed tomography angiography versus the final diagnosis after invasive endotyping. The Seattle Angina Questionnaire summary score and Treatment Satisfaction Questionnaire for Medication were secondary outcomes. RESULTS: Of 322 eligible patients, 250 (77.6%) underwent invasive endotyping; 19 (7.6%) had obstructive coronary disease, 127 (55.0%) had microvascular angina, 27 (11.7%) had vasospastic angina, 17 (7.4%) had both, and 60 (26.0%) had no abnormality. A total of 231 patients (mean age, 55.7 years; 64.5% women) were randomly assigned and followed up (median duration, 19.9 [12.6-26.9] months). The clinician diagnosed vasomotor angina in 51 (44.3%) patients in the intervention group and in 55 (47.4%) patients in the control group. After randomization, patients in the intervention group were 4-fold (odds ratio, 4.05 [95% CI, 2.32-7.24]; P<0.001) more likely to be diagnosed with a coronary vasomotor disorder; the frequency of this diagnosis increased to 76.5%. The frequency of normal coronary function (ie, no vasomotor disorder) was not different between the groups before randomization (51.3% versus 50.9%) but was reduced in the intervention group after randomization (23.5% versus 50.9%, P<0.001). At 6 and 12 months, the Seattle Angina Questionnaire summary score in the intervention versus control groups was 59.2±24.2 (2.3±16.2 change from baseline) versus 60.4±23.9 (4.6±16.4 change) and 63.7±23.5 (4.7±14.7 change) versus 66.0±19.3 (7.9±17.1 change), respectively, and not different between groups (global P=0.36). Compared with the control group, global treatment satisfaction was higher in the intervention group at 12 months (69.9±22.8 versus 61.7±26.9, P=0.013). CONCLUSIONS: For patients with angina and no obstructive coronary arteries, a diagnosis informed by invasive functional assessment had no effect on long-term angina burden, whereas treatment satisfaction improved. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03477890.

ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial.

BACKGROUND: Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy. METHODS: Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379). RESULTS: Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; P<0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; P=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; P=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; P=0.549). CONCLUSIONS: Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.

Primary versus iatrogenic (post-PCI) coronary microvascular dysfunction: a wire-based multimodal comparison.

BACKGROUND: Although there are studies examining each one separately, there are no data in the literature comparing the magnitudes of the iatrogenic, percutaneous coronary intervention (PCI)-induced, microvascular dysfunction (Type-4 CMD) and coronary microvascular dysfunction (CMD) in the setting of ischaemia in non-obstructed coronary arteries (INOCA) (Type-1 CMD). OBJECTIVES: We aimed to compare the characteristics of Type-1 and Type-4 CMD subtypes using coronary haemodynamic (resistance and flow-related parameters), thermodynamic (wave energy-related parameters) and hyperemic ECG changes. METHODS: Coronary flow reserve (CFR) value of <2.5 was defined as CMD in both groups. Wire-based multimodal perfusion markers were comparatively analysed in 35 patients (21 INOCA/CMD and 14 CCS/PCI) enrolled in NCT05471739 study. RESULTS: Both groups had comparably blunted CFR values per definition (2.03±0.22 vs 2.11±0.37; p: 0.518) and similar hyperemic ST shift in intracoronary ECG (0.16±0.09 vs 0.18±0.07 mV; p: 0.537). While the Type-1 CMD was characterised with impaired hyperemic blood flow acceleration (46.52+12.83 vs 68.20+28.63 cm/s; p: 0.017) and attenuated diastolic microvascular decompression wave magnitudes (p=0.042) with higher hyperemic microvascular resistance (p<0.001), Type-4 CMD had blunted CFR mainly due to higher baseline flow velocity due to post-occlusive reactive hyperemia (33.6±13.7 vs 22.24±5.3 cm/s; p=0.003). CONCLUSIONS: The perturbations in the microvascular milieu seen in CMD in INOCA setting (Type-1 CMD) seem to be more prominent than that of seen following elective PCI (Type-4 CMD), although resulting reversible ischaemia is equally severe in the downstream myocardium.

[Outcome indicators in clinical trials on traditional Chinese medicine treatment of microvascular angina].

This study reviewed the current status of the use of outcome indicators in randomized controlled trial(RCT) on traditional Chinese medicine(TCM) treatment of microvascular angina(MVA) and analyzed the existing problems and possible solutions, aiming to provide a basis for the design of high-quality RCT and the establishment of core outcome sets for MVA. CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, and 2 clinical trial registries were searched for the RCT on TCM treatment of MVA according to pre-defined criteria. The Cochrane's risk of bias assessment tool was used to evaluate the methodological quality of the included RCT and the use of outcome indicators was summarized. A total of 69 RCTs were included, from which 100 outcome indicators were extracted, with the frequency of 430. The extracted outcome indicators belonged to 8 domains: response rate, symptoms and signs, physical and chemical examinations, TCM efficacy, safety, quality of life, economic evaluation, and long-term prognosis. The indicators of physical and chemical examinations were the most(70 indicators with the frequency of 211), followed by those of response rate(7 indicators with the frequency of 73) and symptoms and signs(7 indicators with the frequency of 54). The outcome indicators with higher frequency were adverse reactions, angina attack frequency, clinical efficacy, endothelin-1, total duration of treadmill exercise, and hypersensitive C-reactive protein. The RCT on TCM treatment of MVA had the following problems: irregular reporting of adverse reactions, diverse indicators with low frequency, lack of attention to the application of endpoint indicators, insufficient use of TCM differentiation and efficacy indicators, non-standard evaluation criteria and failure to reflect the basic characteristics of TCM. A unified MVA syndrome differentiation standard should be established, on the basis of which an MVA treatment efficacy evaluation system and core outcome indicator set that highlights the characteristics of TCM with patient-reported outcomes as the starting point should be established to improve the clinical research and research value.

The relationships between acetylcholine-induced chest pain, objective measures of coronary vascular function and symptom status.

Background: Acetylcholine-induced chest pain is routinely measured during the assessment of microvascular function. Aims: The aim was to determine the relationships between acetylcholine-induced chest pain and both symptom burden and objective measures of vascular function. Methods: In patients with angina but no obstructive coronary artery disease, invasive studies determined the presence or absence of chest pain during both acetylcholine and adenosine infusion. Thermodilution-derived coronary blood flow (CBF) and index of microvascular resistance (IMR) was determined at rest and during both acetylcholine and adenosine infusion. Patients with epicardial spasm (>90%) were excluded; vasoconstriction between 20% and 90% was considered endothelial dysfunction. Results: Eighty-seven patients met the inclusion criteria. Of these 52 patients (60%) experienced chest pain during acetylcholine while 35 (40%) did not. Those with acetylcholine-induced chest pain demonstrated: (1) Increased CBF at rest (1.6 ± 0.7 vs. 1.2 ± 0.4, p = 0.004) (2) Decreased IMR with acetylcholine (acetylcholine-IMR = 29.7 ± 16.3 vs. 40.4 ± 17.1, p = 0.004), (3) Equivalent IMR following adenosine (Adenosine-IMR: 21.1 ± 10.7 vs. 21.8 ± 8.2, p = 0.76), (4) Increased adenosine-induced chest pain (40/52 = 77% vs. 7/35 = 20%, p < 0.0001), (5) Increased chest pain during exercise testing (30/46 = 63% vs. 4/29 = 12%, p < 0.00001) with no differences in exercise duration or electrocardiographic changes, and (6) Increased prevalence of epicardial endothelial dysfunction (33/52 = 63% vs. 14/35 = 40%, p = 0.03). Conclusions: After excluding epicardial spasm, acetylcholine-induced chest pain is associated with increased pain during exercise and adenosine infusion, increased coronary blood flow at rest, decreased microvascular resistance in response to acetylcholine and increased prevalence of epicardial endothelial dysfunction. These findings raise questions about the mechanisms underlying acetylcholine-induced chest pain.