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Background: The relationship between atherosclerosis and endotypes of myocardial ischaemia with no obstructive coronary artery disease (INOCA) is unclear. We investigated potential associations between cumulative atherosclerotic plaque burden quantified using the Gensini score, novel invasive indices of coronary microvascular function (microvascular resistance reserve (MRR); resistive reserve ratio (RRR)) and related INOCA endotypes., Methods: Coronary angiography and invasive coronary function tests were simultaneously acquired in the CorMicA cohort. A comprehensive physiological assessment was performed using both a thermodilution-based diagnostic guidewire and intracoronary acetylcholine provocation testing. Angiograms were examined for luminal stenosis in each segment of the SYNTAX coronary model. Cumulative plaque burden was quantified using the Gensini score, which incorporated both the number of diseased coronary segments and stenosis severity. Results were compared with indices of microvascular function and INOCA endotypes. Angiographic analyses were performed blind to coronary physiology findings., Results: In 151 participants (median age 61 years; 73.5% female) without flow-limiting coronary artery disease, medical history included 41.7% smoking, 63.6% hypertension and 19.2% diabetes mellitus. The left anterior descending artery underwent diagnostic guidewire testing in 85.4%, and 55.0% of participants had abnormal coronary flow reserve (CFR) and/or Index of Microcirculatory Resistance (IMR). The median Gensini score was 6.0 (IQR 2.5-11.0). CFR (p=0.012), MRR (p=0.026) and RRR (p=0.026), but not IMR (p=0.445), were univariably associated with raised Gensini scores. These significant effects persisted in multivariable models controlling for potential confounders. Considering INOCA endotypes, Gensini scores differed among participants with microvascular angina (MVA) (7.0 (2.5-11.0)), vasospastic angina (VSA) (4.5 (2.0-10.0)), mixed MVA/VSA (9.0 (5.0-11.5)) and non-cardiac symptoms (3.5 (1.5-8.0)); Kruskal-Wallis p=0.030., Conclusions: Reduced CFR, MRR and RRR, and MVA were associated with increased coronary atherosclerotic plaque burden, as evidenced by higher Gensini scores. These novel findings provide a mechanistic link between INOCA and cardiovascular events, reinforcing the importance of antiatherosclerosis therapy in patients with MVA., Competing Interests: Competing interests: Dr TF received consulting fees from BioExcel; honoraria from Abbott, Boehringer, Novartis. Dr SW received honoraria from Abbott, AstraZeneca, Biosensors, Boston Scientific, Daiichi Sankyo, GE Healthcare and ShockWave Medical. Dr KR received honoraria from AstraZeneca and Abbott. Dr MM received consulting fees from Abbott, Boston Scientific and ShockWave Medical; honoraria from International Medical Device Solutions and Medtronic. Dr KGO received honoraria from Abbott, Biosensors International and Boston Scientific; full-time employee of Biosensors International since May 2020. Dr CB receives research funding from the British Heart Foundation grant (RE/18/6134217, PG/19/28/34310), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1) and Medical Research Council (MR/S018905/1). None of the declared interests regards the submitted work. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Competing Interests: Declaration of competing interest Dr Berry receives research funding from the British Heart Foundation grant (RE/18/6134217), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1), Medical Research Council (MR/S018905/1) and UKRI (MC/PC/20014). None of the other authors have any potential conflicts of interest.

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., Competing Interests: Disclosures Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements with companies that have interests in the management of angina. The companies include Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Coroventis, HeartFlow, Novartis, Siemens Healthcare, Therox, and Valo Health. Dr McEntegart provides consultancy for Biosensors, Boston Scientific, Shockwave Medical and Teleflex, and has received honoraria from Biosensors, Boston Scientific and Medtronic. Dr Ford provides consultancy for Abbott Vascular. None of the other authors have any potential conflicts of interest.

Approximately 40% of patients undergoing invasive coronary angiography for investigation of angina are found to have no obstructive coronary artery disease (ANOCA). Abnormal coronary function underlies coronary vasomotion syndromes including coronary endothelial dysfunction, microvascular angina, vasospastic angina, post-PCI angina and myocardial infarction with no obstructive coronary arteries (MINOCA). Each of these endotypes are distinct subgroups, characterized by specific disease mechanisms. Diagnostic criteria and linked therapy for these conditions are now established by expert consensus and clinical guidelines. Coronary function tests are performed as an adjunctive interventional diagnostic procedure (IDP) in appropriately selected patients during coronary angiography. This aids differentiation of patients according to endotype. The IDP includes two distinct components: a diagnostic guidewire test and a pharmacological coronary reactivity test. The tests last approximately 5 minutes for the former and 10-15 minutes for the latter. Patient safety and staff education are key. The diagnostic guidewire test measures parameters of coronary flow limitation (fractional flow reserve [FFR], coronary flow reserve [CFR], microvascular resistance [index of microvascular resistance (IMR)], basal resistance index, and vasodilator function [CFR, resistive reserve ratio (RRR)]). The pharmacological coronary reactivity test measures the vasodilator potential and propensity to vasospasm of both the main coronary arteries and the micro-vessels. It involves intra-coronary infusion of acetylcholine and glyceryl trinitrate (GTN). Acetylcholine is not licensed for parenteral use and is therefore prescribed on a named-patient basis. Vasodilatation is the normal, expected response to infusion of physiological concentrations of acetylcholine. Vascular spasm represents an abnormal response, which supports the diagnosis of vasospastic angina. The purpose of this practical guide is to provide information on the preparation and administration of the IDP in clinical practice. It discusses some key preparation and safety considerations, as well as tips for procedural success. The IDP supports stratified medicine for a personalized approach to health and wellbeing.

Background: Coronary artery bypass graft (CABG) patients are under-represented in acute coronary syndrome (ACS) trials. We compared characteristics and outcomes for patients who did and did not participate in a randomised trial of invasive versus non-invasive management (CABG-ACS)., Methods: ACS patients with prior CABG in four hospitals were randomised to invasive or non-invasive management. Non-randomised patients entered a registry. Primary efficacy (composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction (MI), heart failure) and safety outcomes (composite of bleeding, stroke, procedure-related MI, worsening renal function) were independently adjudicated., Results: Of 217 patients screened, 84 (39%) screenfailed, of whom 24 (29%) did not consent and 60 (71%) were ineligible. Of 133 (61%) eligible, 60 (mean±SD age, 71±9 years, 72% male) entered the trial and 73 (age, 72±10 years, 73% male) entered a registry (preferences: physician (79%), patient (38%), both (21%)).Compared with trial participants, registry patients had more valve disease, lower haemoglobin, worse New York Heart Association class and higher frailty.At baseline, invasive management was performed in 52% and 49% trial and registry patients, respectively, of whom 32% and 36% had percutaneous coronary intervention at baseline, respectively (p=0.800). After 2 years follow-up (694 (median, IQR 558-841) days), primary efficacy (43% trial vs 49% registry (HR 1.14, 95% CI 0.69 to 1.89)) and safety outcomes (28% trial vs 22% registry (HR 0.74, 95% CI 0.37 to 1.46)) were similar. EuroQol was lower in registry patients at 1 year., Conclusions: Compared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar., Trial Registration Number: NCT01895751., Competing Interests: Competing interests: CB is employed by the University of Glasgow, which holds consultancy and/or research agreements with companies that have commercial interests in the diagnosis and treatment of ischaemic heart disease, including Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, HeartFlow, Menarini Farmaceutica, Opsens, Philips and Siemens Healthcare. There are no other relevant personal disclosures., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Ischaemic heart disease is a leading cause of mortality in women. Even in those without obstructive coronary artery disease (CAD), women with angina continue to have increased mortality. There are gender differences in prevalence of different pathophysiologies, including functional disorders such as microvascular and vasospastic angina., Case Summary: We describe four cases of angina in women with no obstructive CAD, in whom coronary function testing was performed. These four patients were diagnosed with disorders of coronary vasomotion, including vasospastic angina and different endotypes of microvascular angina., Discussion: This case series highlights the different mechanisms of ischaemia in the absence of obstructive CAD. Patients with angina and no obstructive CAD classified by computed tomography coronary angiography may have myocardial ischaemia due to microvascular angina, vasospastic angina, or both. Conventional investigations risk under-diagnosing, and as a consequence under-treating, patients with these conditions. Coronary function testing, in the form of diagnostic guidewire-based tests and adjunctive acetylcholine provocation, has proven to be critical in the accurate diagnoses and appropriate management of these patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Microvascular and/or vasospastic anginas are relevant causes of ischemia with no obstructive coronary artery disease (INOCA) in patients after computed tomography coronary angiography (CTCA)., Objectives: Our research has 2 objectives. The first is to undertake a diagnostic study, and the second is to undertake a nested, clinical trial of stratified medicine., Design: A prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03477890) will be performed. All-comers referred for clinically indicated CTCA for investigation of suspected coronary artery disease (CAD) will be screened in 3 regional centers. Following informed consent, eligible patients with angina symptoms are enrolled before CTCA and remain eligible if CTCA excludes obstructive CAD. Diagnostic study: Invasive coronary angiography involving an interventional diagnostic procedure (IDP) to assess for disease endotypes: (1) angina due to obstructive CAD (fractional flow reserve ≤0.80); (2) microvascular angina (coronary flow reserve <2.0 and/or index of microvascular resistance >25); (3) microvascular angina due to small vessel spasm (acetylcholine); (4) vasospastic angina due to epicardial coronary spasm (acetylcholine); and (5) noncoronary etiology (normal coronary function). The IDP involves direct invasive measurements using a diagnostic coronary guidewire followed by provocation testing with intracoronary acetylcholine. The primary outcome of the diagnostic study is the reclassification of the initial CTCA diagnosis based on the IDP. Stratified medicine trial: Participants are immediately randomized 1:1 in the catheter laboratory to therapy stratified by endotype (intervention group) or not (control group). The primary outcome of the trial is the mean within-subject change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and certainty), and clinical utility (impact on treatment and investigations). Health status assessments include quality of life, illness perception, anxiety-depression score, treatment satisfaction, and physical activity. Participants who are not randomized will enter a follow-up registry. Health and economic outcomes in the longer term will be assessed using electronic patient record linkage., Value: CorCTCA will prospectively characterize the prevalence of disease endotypes in INOCA and determine the clinical value of stratified medicine in this population., Competing Interests: Disclosures Prof Colin Berry is employed by the University of Glasgow, which holds consultancy and research agreements with companies that have interests in the diagnosis and treatment of angina. The companies include Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Coroventis, HeartFlow, and Siemens Healthcare. Prof Keith G. Oldroyd has received consultant and speaker fees from Abbott Vascular. Prof Olivia Wu holds consultancy agreement with Bayer and have received consultancy fees from Takeda and Lupin. None of these companies have had any involvement with this study. None of the other authors have any potential conflicts of interest. The authors are solely responsible for the design of this study, all study analyses, the drafting and editing of the paper, and its final contents., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials., Methods: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function)., Results: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years' follow-up (median [interquartile range], 744 [570-853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months., Conclusions: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01895751.

Aims: To compare the effect of the direct renin inhibitor aliskiren on neurohumoral activity in heart failure patients treated with low-dose and high-dose ACE inhibitor., Methods: A retrospective analysis of the ALOFT trial. Comparison of the effects of 6 months treatment with aliskiren (versus placebo) in patients receiving

Aims: Southeast Asia is endemic for Brugada syndrome; however, its prevalence in Singapore is unknown. We aimed to determine the prevalence of Brugada sign [Types 1, 2, and 3 Brugada electrocardiogram (ECG)] and syndrome at an arrhythmia clinic in Singapore., Methods and Results: Patients who presented with pre-syncope, syncope, and/or palpitations without a known cause at an arrhythmia clinic between 2005 and 2007 were included in the study. The study criteria were met by 392 patients (age: 49.6 +/- 19.1 years, 55.9% male); 675 patients were excluded because they were referred for the management of known diagnoses. The 12-lead ECGs of these patients were analysed and clinical information was abstracted. Brugada sign was observed in 28 patients, and 12 patients were determined to have Brugada syndrome (age: 36.3 +/- 15.4 years, 100% male), yielding a prevalence of 7.1% [95% confidence interval (CI): 4.8-10.2] and 3.1% (95% CI: 1.6-5.3), respectively. The prevalence rates of patients with Type 1, Type 2, and Type 3 Brugada signs were 4.8% (95% CI: 2.9-7.5), 1.8% (95% CI: 0.7-3.6), and 0.5% (95% CI: 0.06-1.8), respectively. Over 30.4 person-years of follow-up, there was one inappropriate defibrillation shock but no appropriate shocks or sudden cardiac deaths among patients with Brugada sign or syndrome., Conclusion: The prevalence of both Brugada sign and syndrome in a hospital-based population in Singapore was found to be high. Further population-based investigation is warranted to confirm these findings.

Purpose: To study the characteristics, outcomes and prognostic markers of convulsive status epilepticus (SE) in Singapore., Methods: 62 adult admissions to the National University Hospital Singapore from 2002 to 2005 were studied. Ethnicity, history of epilepsy, educational subnormality, neuroimaging, seizure duration, length of stay, Modified Rankin Scale (MRS) pre and post discharge, blood glucose, creatine kinase, potassium, white cell and platelet count were recorded. An MRS> or =3 at discharge was defined as a poor outcome. ROCs of significant variables were plotted to identify the best test cut-offs., Results: Mean age was 59.2 years (range 20-94). 75.9% patients had epilepsy. Mean length of stay was 14 days (range 1-75). Univariate analyses revealed age (p=0.01, OR 1.075, 95% CI 1.030-1.122), length of stay in ICU (p=0.03, OR 1.299, 95% CI 1.014-1.665) and hospital (p=0.014, OR 1.203, 95% CI 1.038-1.393) and hyperglycemia (p=0.045, OR 1.327, 95% CI 1.007-1.750) associated with poor outcome. Test cut-off values for prognostic markers were established: age> or =55 years (ROC 0.790, sensitivity 72.3, specificity 85.7, PPV9 4.4%, NPV 48.8%) and serum glucose> or =7 mmol/L (ROC 0.737, sensitivity 72.3, specificity 80.0, PPV 93.5%, NPV 36.4%). A discriminant model using these variables was then constructed with probability scores for poor outcome., Discussion: Age, hyperglycemia and length of stay in hospital influenced outcome from convulsive SE in the local population with hyperglycemia being a novel prognostic marker. Some prognostic markers cited in the literature differed, highlighting the possibility that these indicators may vary across population groups.