Open access and its potential impact on public health - A South African perspective.

Traditionally, access to research information has been restricted through journal subscriptions. This means that research entities and individuals who were unable to afford subscription costs did not have access to journal articles. There has however been a progressive shift toward electronic access to journal publications and subsequently growth in the number of journals available globally. In the context of electronic journals, both open access and restricted access options exist. While the latter option is comparable to traditional, subscription-based paper journals, open access journal publications follow an "open science" publishing model allowing scholarly communications and outputs to be publicly available online at no cost to the reader. However, for readers to enjoy open access, publication costs are shifted elsewhere, typically onto academic institutions and authors. SARS-CoV-2, and the resulting COVID-19 pandemic have highlighted the benefits of open science through accelerated research and unprecedented levels of collaboration and data sharing. South Africa is one of the leading open access countries on the African continent. This paper focuses on open access in the South African higher education research context with an emphasis on our Institution and our own experiences. It also addresses the financial implications of open access and provides possible solutions for reducing the cost of publication for researchers and their institutions. Privacy in open access and the role of the Protection of Personal Information Act (POPIA) in medical research and secondary use of data in South Africa will also be discussed.

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

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

Different vasoreactivity of arterial bypass grafts versus native coronary arteries in response to acetylcholine.

BACKGROUND: Coronary angiography is often performed in patients with recurrent angina after successful coronary artery bypass grafting (CABG) in search of the progression of atherosclerosis. However, in many of these patients, no relevant stenosis can be detected. We speculate that coronary spasm may be associated with angina in these patients. METHODS: From 2307 patients with unobstructed coronaries who underwent intracoronary acetylcholine spasm provocation testing (ACh-test) between 2012 and 2016, 54 consecutive patients who fulfilled the following inclusion criteria were included in this cohort study: previous left internal thoracic artery (LITA) bypass on the left anterior descending (LAD) coronary artery, ongoing/recurrent angina pectoris, no significant (< 50%) coronary artery or bypass stenosis. In all participants, the ACh-test was performed via the LITA bypass. RESULTS: In 14 patients (26%) the ACh-test elicited epicardial spasm of the LAD distal to the anastomosis (≥ 90% diameter reduction with reproduction of the patient's symptoms and ischemic ECG shifts). Microvascular spasm (reproduction of symptoms and ischemic ECG-changes but no epicardial spasm) was seen in 30 patients (55%). The ACh-test was normal in the remaining 10 patients (19%). ACh-testing did not elicit any relevant vasoconstriction in the LITA bypasses in contrast to the LAD on quantitative coronary analyses (4.89 ± 7.36% vs. 52.43 ± 36.07%, p < 0.01). CONCLUSION: Epicardial and microvascular coronary artery spasm are frequent findings in patients with ongoing or recurrent angina after CABG but no relevant stenosis. Vasoreactivity to acetylcholine is markedly different between LITA bypasses and native LAD arteries with vasoconstriction almost exclusively occurring in the LAD.

Long-Term Follow-Up in Patients With Stable Angina and Unobstructed Coronary Arteries Undergoing Intracoronary Acetylcholine Testing.

OBJECTIVES: The aim of this study was to investigate the prognosis of a large cohort of patients with stable angina and unobstructed coronaries undergoing acetylcholine spasm testing. BACKGROUND: Coronary artery spasm can be found in up to 60% of patients with symptoms of myocardial ischemia despite unobstructed coronary arteries. METHODS: Consecutive symptomatic patients with unobstructed coronary arteries undergoing acetylcholine testing to detect epicardial or microvascular coronary spasm were prospectively enrolled. After a median follow-up period of 7.2 years (6.5 to 7.9 years), data regarding mortality, nonfatal myocardial infarction, stroke, repeat coronary angiography, recurrent symptoms, and quality of life were obtained in 736 patients (57% women, mean age 62 ± 12 years). RESULTS: In total, 55 deaths (7.5%), 8 nonfatal myocardial infarctions (1.4%), and 12 strokes (2.2%) occurred during the follow-up period. Recurrent symptoms were reported by 64% of patients, and repeat coronary angiography was performed in 12% of cases. Multivariate analysis revealed epicardial spasm as a predictor of nonfatal myocardial infarction (hazard ratio: 14.469; 95% confidence interval: 1.735 to 120.646) and repeat angiography (hazard ratio: 1.703; 95% confidence interval: 1.062 to 2.732), whereas patients with microvascular spasm more often had recurrent angina at follow-up (hazard ratio: 1.311; 95% confidence interval: 1.013 to 1.697). CONCLUSIONS: In this long-term follow-up study, the overall prognosis of patients with coronary spasm was favorable. Patients with epicardial spasm were at increased risk for myocardial infarction and repeat angiography, while microvascular spasm was associated with recurrent angina. Acetylcholine testing may help identify patients at increased risk for adverse cardiac events among this overall low-risk population.

Prognostic implications of coronary artery stenosis and coronary spasm in patients with stable angina: 5-year follow-up of the Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries (ACOVA) study.

BACKGROUND: In the Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries study, we showed that 62% of patients with stable angina and unobstructed coronary arteries had coronary spasm. In this study, we sought to assess the 5-year prognosis in these patients. METHODS: Data regarding the following endpoints were obtained: death, non-fatal myocardial infarction, coronary event (=cardiac death or non-fatal myocardial infarction), persistent angina and repeated coronary angiography. Quality of life was assessed using the Seattle Angina Questionnaire. RESULTS: Among patients with unobstructed coronary arteries there were three deaths (2.9%) and no non-fatal myocardial infarction. Among those with obstructive CAD 15 died (13.8%) and three had a non-fatal myocardial infarction (2.8%). Patients with obstructive CAD had a higher rate of all-cause death and coronary events compared to those without (P = 0.004). Persistent angina was more prevalent in patients with unobstructed coronaries (P = 0.042). Prognosis of patients with unobstructed coronaries regarding hard clinical events, persistent angina and repeated coronary angiography was independent of the presence of coronary spasm (all P > 0.05). However, spasm patients were more likely to take nitrate medication at follow-up (P = 0.029). CONCLUSION: Patients with stable angina and unobstructed coronary arteries have a favorable prognosis regarding mortality and non-fatal myocardial infarction after 5 years compared to patients with obstructive CAD irrespective of the presence of coronary artery spasm. However, persistent angina remains a common issue in patients with unobstructed coronary arteries leading to a similar frequency of repeated invasive procedures as in patients with obstructive CAD.

Microvascular spasm in non-ST-segment elevation myocardial infarction without culprit lesion (MINOCA).

BACKGROUND: Up to 30% of patients with acute coronary syndrome have no culprit lesion. Coronary microvascular spasm is an alternative cause for such a clinical presentation. However, this has rarely been investigated systematically. The aim of our study was to assess the frequency of coronary microvascular spasm in patients with NSTEMI without culprit lesion (MINOCA) by intracoronary acetylcholine testing (ACH-test). METHODS: Between 2014 and 2017, 940 patients with NSTEMI underwent coronary angiography and 125 (13%) had no culprit lesion (< 50% stenosis on visual assessment). Of the latter, 29 patients had other causes for the clinical presentation (e.g. tako-tsubo-syndrome or myocarditis). The remaining 96 patients were recruited for the study and underwent ACH-testing according to a standardized protocol. RESULTS: The ACH-test was normal in 40 (42%) and abnormal in the remaining 56 (58%) patients. Of the latter, 26 patients (46%) had epicardial spasm (epicardial narrowing ≥ 90%, reproduction of symptoms and ischemic ST-segment changes) and 30 (54%) microvascular spasm (ischemic ST-shifts and angina without epicardial vasoconstriction ≥ 90%). The peak high-sensitive troponin-T concentration was 113 (42-255) pg/ml. Patients with coronary spasm had more often a positive family history compared to those without and patients with epicardial compared to microvascular spasm were more often smokers. CONCLUSION: Coronary microvascular spasm is frequently found in patients with NSTEMI without culprit lesion and represents a likely cause of myocardial injury. ACH-testing is useful for detection of vasomotor disorders allowing tailored treatment with calcium antagonists and/or nitrates in addition to secondary prevention to improve symptoms and prognosis. Microvascular spasm in non-ST-segment elevation myocardial infarction without culprit lesion (MINOCA) .

Epicardial Coronary Spasm in Women With Angina Pectoris and Unobstructed Coronary Arteries Is Linked With a Positive Family History: An Observational Study.

PURPOSE: Coronary spasm is frequently found in patients with angina and unobstructed coronaries. The pathophysiology is incompletely understood, although sex differences have been described. Often a positive family history (PFH) is encountered. We assessed the relationship between sex, coronary spasm, and a PFH for cardiovascular disease. METHODS: This single-center observational study recruited 415 stable angina patients with unobstructed coronaries (no stenosis >50%) between 2008 and 2011 (mean [SD] age, 62 [10] years; 38% men). Patients were referred for angiography because of signs and symptoms of myocardial ischemia. Intracoronary acetylcholine (ACh) testing was performed in all patients according to a standardized protocol. Risk factor assessment included hypertension, hypercholesterolemia, diabetes, smoking, and a PFH. The latter was defined as a first-degree relative with myocardial infarction or stroke. Statistical analysis involved comparison of categorical and continuous variables. Multivariable analysis aimed at identifying predictors for a pathologic ACh testing, microvascular spasm, and a PFH. FINDINGS: Epicardial spasm was found in 33% of patients and microvascular spasm in 30% of patients. A pathologic ACh test was more frequent in women than in men (72% vs 49%; P < 0.0005). A PFH was found in 55% of patients with significantly more women than men (61% vs 45%; P = 0.001). Among patients with epicardial spasm, women had a PFH significantly more often than men (66% vs 43%; P = 0.006). The latter difference was not found when comparing women and men with microvascular spasm. IMPLICATIONS: There is a female preponderance among patients with angina and unobstructed coronaries. ACh testing enables detection of coronary spasm. Epicardial spasm in women is associated with a PFH.

Biopsy-confirmed endothelial cell activation in patients with coronary microvascular dysfunction.

BACKGROUND: Patients with angina yet having unobstructed coronaries are found in ∼50% of cases undergoing invasive angiography. Coronary spasm and microvascular dysfunction can be responsible for the clinical presentation in ∼60% of cases. However, little is known about structural changes in the myocardium. The aim of this study was to describe findings in endomyocardial biopsies of symptomatic patients with unobstructed coronaries. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 1416 consecutive patients who underwent endomyocardial biopsy sampling and coronary angiography between 2002 and 2016 for various clinical indications. Of them, 309 patients had also undergone intracoronary acetylcholine testing (ACH-test). To be eligible for the study, patients had to have normal left ventricular ejection fraction, unobstructed coronaries and absence of viral genomes in the myocardium. RESULTS: Among the final cohort of 33 (70% female, mean age 53) patients, the ACH-test revealed coronary microvascular spasm in 11 (33.3%) patients. Twelve (36.4%) patients had epicardial spasm and 10 (30.3%) had an uneventful ACH-test. Immunohistology revealed activated macrophages in 10 (30%) cases and activated endothelial cells as well as perivascular or interstitial fibrosis in 17 (52%). Myocardial hypertrophy was seen in nine (27%) patients, and smooth muscle cell proliferation was present in 11 (33%) cases. Compared with the rest of the cohort, patients with microvascular spasm significantly more often had activated endothelial cells (P=0.003). CONCLUSION: This study gives unique insights into structural myocardial alterations in patients with angina, unobstructed coronaries and abnormal coronary vasomotion, suggesting that a combination of both structural and functional alterations is frequent.

Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders.

Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the catheterization laboratory which was introduced more than 30 years ago. Due to the short half-life of acetylcholine it can only be applied directly into the coronary arteries. Several studies have demonstrated the safety and clinical usefulness of this test. However, acetylcholine testing is only rarely applied in the U.S. or Europe. Nevertheless, it has been shown that 62% of Caucasian patients with stable angina and unobstructed coronary arteries on coronary angiography suffer from coronary vasomotor disorders that can be diagnosed with acetylcholine testing. In recent years it has been appreciated that the ACH-test not only assesses the presence of epicardial spasm but that it can also be useful for the detection of coronary microvascular spam. In such cases no epicardial spasm is seen after injection of acetylcholine but ischemic ECG shifts are present together with a reproduction of the patient's symptoms during the test. This article describes the experience with the ACH-test and its implementation in daily clinical routine.

Treatment of Angina Pectoris Associated with Coronary Microvascular Dysfunction.

Treatment of angina pectoris associated with coronary microvascular dysfunction is challenging as the underlying mechanisms are often diverse and overlapping. Patients with type 1 coronary microvascular dysfunction (i.e. absence of epicardial coronary artery disease and myocardial disease) should receive strict control of their cardiovascular risk factors and thus receive statins and ACE-inhibitors in most cases. Antianginal medication consists of ß-blockers and/or calcium channel blockers. Second line drugs are ranolazine and nicorandil with limited evidence. Despite individually titrated combinations of these drugs up to 30 % of patients have refractory angina. Rho-kinase inhibitors and endothelin-receptor antagonists represent potential drugs that may prove useful in these patients in the future.

Interleukin-6 Kinetics can be Useful for Early Treatment Monitoring of Severe Bacterial Sepsis and Septic Shock.

Early appropriate anti-microbial therapy is necessary to improve outcomes of septic patients. We describe 20 case histories of patients with severe bacterial sepsis regarding kinetics of several biomarkers. We found that interleukin-6 is able to predict survival and might be able to evaluate appropriateness of anti-microbial therapy.

Testing in Patients With Stable Coronary Artery Disease　- The Debate Continues.

The major guidelines on stable coronary artery disease recommend revascularizing patients with large areas of myocardium at risk. The algorithms on how to prove that such high risk is present differ considerably. The opinions on the use of coronary CT (calcium scoring and angiography) vary widely. This review aims to summarize the recommendations of the major guidelines, commenting on differences between the guidelines and discussing whether extending the role of coronary CT angiography should be considered in the light of new CT data.

Structural and Functional Coronary Artery Abnormalities in Patients With Vasospastic Angina Pectoris.

Coronary spasm is involved in many clinical scenarios, such as stable angina, acute coronary syndrome, sudden cardiac death, non-ischemic cardiomyopathy, arrhythmia and syncope. In recent years, imaging tools such as computerized tomographic angiography, intravascular ultrasound or optical coherence tomography have been applied to study the coronary pathology in patients with vasospastic angina. Patients with vasospastic angina represent a heterogeneous cohort of patients with regard to the extent of concomitant coronary atherosclerosis. They share the common pathophysiological phenomenon of vascular smooth muscle hyperreactivity leading to spasm caused by various factors that may also overlap. Focal coronary spasm is related to epicardial atherosclerosis and in the presence of obstructive coronary artery disease it may be useful to treat the lesion to prevent further spasm. The aim of this article is to review structural and functional coronary artery abnormalities in patients with vasospastic angina.

Acetylcholine-induced coronary spasm in patients with unobstructed coronary arteries is associated with elevated concentrations of soluble CD40 ligand and high-sensitivity C-reactive protein.

OBJECTIVES: To assess whether epicardial and microvascular coronary artery spasm in response to acetylcholine (ACH) is associated with markers of inflammation, platelet stimulation, and endothelial activation in patients with angina and unobstructed coronary arteries. BACKGROUND: Patients with angina pectoris despite angiographically normal coronary arteries represent a diagnostic and therapeutic challenge. Both impaired coronary microvascular dilatory responses as well as diffuse distal epicardial and microvascular coronary artery spasm have been described as possible pathogenic mechanisms. Although inflammation has been proposed to play a pathogenic role in angina, an association between ACH-induced coronary vasospasm and inflammation in Caucasians has not been reported previously in this context. PATIENTS AND METHODS: We assessed 62 consecutive patients (26 men, age 60±10 years) with chest pain despite angiographically unobstructed coronary arteries (<50% stenosis) who underwent intracoronary ACH testing for the diagnosis of coronary artery spasm. High-sensitivity C-reactive protein (hs-CRP), e-selectin, neopterin, and sCD40L concentrations were measured in all patients before ACH testing. The ACH test was considered to be 'positive' in the presence of (a) angina and at least 75% coronary diameter reduction (epicardial coronary artery spasm) or (b) ischemic ST-shifts and angina in the absence of epicardial spasm (microvascular spasm). Eight patients without angina pectoris served as a control group. RESULTS: The ACH test was positive in 48 patients (77%). Twenty-seven patients had epicardial spasm (56%) and 21 patients had microvascular spasm (44%). Epicardial spasm was diffuse in 26 patients (96%) and focal in one patient (4%). Elevated hs-CRP, e-selectin, and sCD40 ligand concentrations were significantly (P≤0.05) associated with a positive ACH-test response. Hs-CRP (odds ratio 1.54, confidence interval 1.02-2.33, P=0.04) and sCD40 ligand (odds ratio 1.001, confidence interval 1.00-1.001, P=0.003) were predictors for a positive ACH test on multivariate analysis. None of the patients in the control group developed epicardial or microvascular spasm during ACH testing. CONCLUSION: Epicardial and microvascular coronary spasm in response to ACH correlate significantly with hs-CRP and sCD40 ligand concentrations in patients with angina pectoris and angiographically unobstructed coronary arteries. These results suggest that an association exists between inflammation and coronary artery spasm in patients with angina pectoris despite unobstructed coronary arteries and studies are needed to explore the mechanisms underlying this association.

Pharmacotherapy for coronary microvascular dysfunction.

Coronary microvascular dysfunction (CMD) has been increasingly recognized as an important cardiac condition that can cause signs and symptoms of myocardial ischaemia in various clinical settings. The dysfunction is located on the level of the coronary microcirculation with a vessel diameter of <500 µm and can be characterized by structural as well as functional vascular alterations. The underlying mechanisms are diverse, frequently overlapping and still incompletely understood. A common and often underdiagnosed clinical manifestation of CMD is in patients who have angina symptoms yet no obstructive epicardial coronary artery disease nor myocardial disease. There are still very few data regarding the effectiveness of pharmacological treatments for CMD. The current ESC guidelines on the management of stable coronary artery disease suggest using aspirin and statins as well as ß-blockers and/or calcium-channel blockers for the treatment of CMD. This review gives an overview of the currently available pharmacological concepts for the treatment of coronary microvascular dysfunction in patients without epicardial coronary artery disease and without myocardial disease.

Complications in the clinical course of tako-tsubo cardiomyopathy.

OBJECTIVE: This study evaluated the frequency, severity and outcome of complications in the clinical course of tako-tsubo cardiomyopathy (TTC). BACKGROUND: TTC is regarded as a benign disease since left ventricular (LV) function returns to normal within a short time. However, severe complications have been reported in selected patients. METHODS: From 37 hospitals, 209 patients (189 female, age 69 ± 12 years) were prospectively included in a TTC registry. RESULTS: Complications developed in 108/209 patients (52%); 23 (11%) had >2 complications. Complications occurred median 1 day after symptom onset, and 77% were seen within 3 days. Arrhythmias were documented in 45/209 patients (22%) including atrial fibrillation in 32 (15%) and ventricular tachycardia in 17 (8%). Of 8 patients resuscitated (4%), 6 survived. Additional complications were right ventricular involvement (24%), pulmonary edema (13%), cardiogenic shock (7%), transient intraventricular pressure gradients (5%), LV thrombi (3%) and stroke (1%). During hospitalization, 5/209 patients (2.5%) died. Patients with complications were older (70 ± 13 vs 67 ± 10 years, p=0.012), had a higher heart rate (91 ± 26 vs 83 ± 19/min, p=0.025), more frequently Q\ waves on the admission ECG (36% vs 21%, p=0.019) and a lower LV ejection fraction (47 ± 15 vs 54 ± 14%, p = 0.002). Multivariate regression analysis identified Q-waves on admission (OR 2.49, 95% CI 1.23-5.05, p=0.021) and ejection fraction ≤ 30% (OR 4.03, 95% CI 1.04-15.67, p=0.022) as independent predictors for complications. CONCLUSIONS: TTC may be associated with severe complications in half of the patients. Since the majority of complications occur up to day 3, monitoring is advisable for this time period.

Coronary microvascular dysfunction assessed by intracoronary acetylcholine provocation testing is a frequent cause of ischemia and angina in patients with exercise-induced electrocardiographic changes and unobstructed coronary arteries.

BACKGROUND: The exercise electrocardiogram (ECG) is a standard examination in patients with suspected coronary artery disease. However, despite a pathologic result, many patients undergoing diagnostic coronary angiography do not have any significant epicardial stenosis. In this study, we assessed the relation between a pathologic exercise ECG and coronary microvascular dysfunction in response to intracoronary acetylcholine (ACh) provocation in patients without any relevant epicardial stenosis. HYPOTHESIS: Coronary microvascular dysfunction is significantly more often in patients with angina, unobstructed coronary arteries and a pathologic exercise stress test compared to those without pathologic stress test. METHODS: This study recruited 137 consecutive patients with exertional angina pectoris who underwent diagnostic coronary angiography between September 2008 and April 2011 (68% women; mean age, 63 ± 10 years). In none of the patients was there a stenosis of >50%. All patients underwent an exercise ECG before angiography and intracoronary ACh provocation testing for assessment of coronary vasomotor responses directly after angiography. RESULTS: The exercise ECG showed an abnormal result in 69 patients (50%; ST-segment depression ≥0.1 mV and/or reproduction of the patient's usual symptoms). The ACh test revealed a coronary vasomotor abnormality (reproduction of the patient's symptoms, ischemic ECG shifts ± diffuse distal vasoconstriction) in 87 patients (64%). Such a result was significantly more often found in patients with a pathologic exercise ECG (50/69 [72%] vs 19/69 [28%], P = 0.034). There were no other statistically significant differences between patients with and those without pathologic exercise ECG. CONCLUSIONS: Coronary microvascular dysfunction is frequently found in patients with exertional angina pectoris and unobstructed coronary arteries. Such a finding is found significantly more often in presence of a pathologic exercise ECG.

Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries.

BACKGROUND: Coronary spasm can cause myocardial ischemia and angina in patients with and those without obstructive coronary artery disease. However, provocation tests using intracoronary acetylcholine administration are rarely performed in clinical routine in the United States and Europe. Thus, we assessed the clinical usefulness, angiographic characteristics, and safety of intracoronary acetylcholine provocation testing in white patients with unobstructed coronary arteries. METHODS AND RESULTS: From September 2007 to June 2010, a total of 921 consecutive patients (362 men, mean age 62±12years) who underwent diagnostic angiography for suspected myocardial ischemia and were found to have unobstructed coronary arteries (no stenosis ≥50%) were enrolled. The intracoronary acetylcholine provocation testing was performed directly after angiography according to a standardized protocol. Three hundred forty-six patients (35%) reported chest pain at rest, 222 (22%) reported chest pain on exertion, 238 (24%) reported a combination of effort and resting chest pain, and 41 (4%) presented with troponin-positive acute coronary syndrome. The overall frequency of epicardial spasm (>75% diameter reduction with angina and ischemic ECG shifts) was 33.4%, and the overall frequency of microvascular spasm (angina and ischemic ECG shifts without epicardial spasm) was 24.2%. Epicardial spasm was most often diffuse and located in the distal coronary segments (P<0.01). No fatal or irreversible nonfatal complications occurred. However, 9 patients (1%) had minor complications (nonsustained ventricular tachycardia [n=1], fast paroxysmal atrial fibrillation [n=1], symptomatic bradycardia [n=6], and catheter-induced spasm [n=1]). CONCLUSIONS: Epicardial and microvascular spasm are frequently found in white patients with unobstructed coronary arteries. Epicardial spasm is most often diffuse and located in the distal coronary segments. The intracoronary acetylcholine provocation test is a safe technique to assess coronary vasomotor function.