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Coronary microvascular dysfunction (CMD) is a common cause of ischemia but no obstructive coronary artery disease that results in an inability of the coronary microvasculature to meet myocardial oxygen demand. CMD is challenging to diagnose and manage due to a lack of mechanistic research and targeted therapy. Recent evidence suggests we can improved patient outcomes by stratifying antianginal therapies according to the diagnosis revealed by invasive assessment of the coronary microcirculation. This review article appraises the evidence for management of CMD, which includes treatment of cardiovascular risk, antianginal therapy and therapy for atherosclerosis.

Spontaneous coronary artery dissection (SCAD) is an under-recognised cause of acute coronary syndrome (ACS) with a strong female predominance. There are currently limited prospective studies and no randomised controlled trials that inform on SCAD's best clinical care. Little is also known about predictors of acute SCAD deterioration or recurrence. We describe the study design of a multi-centre prospective and historical cohort study recruiting patients with SCAD across 15-20 sites in Australia/New Zealand (NZ). The primary aim is to describe the clinical presentation, management and outcomes along with predictors of acute deterioration and recurrence in a large Australian/NZ SCAD cohort, with international data pooling.Consented patients diagnosed with SCAD during a hospital admission for an ACS will be prospectively followed at 30 days then yearly, for up to 5 years. Each recruiting site will also retrospectively identify historical cases of SCAD from the proceeding 10 years, with a waiver of consent. For historical cases, data will be collected in a de-identified manner with date of last follow-up or death obtained from the medical records. All cases undergo core laboratory adjudication of coronary angiography and any accompanying imaging to confirm SCAD diagnosis. The primary endpoint will be occurrence of major adverse cardiovascular events; a composite of all-cause mortality, recurrent myocardial infarction (including SCAD recurrence), stroke/transient ischaemic attack, heart failure, cardiogenic shock, cardiac arrest/ventricular arrhythmia, heart transplantation and, repeat/unplanned revascularisation. Secondary endpoints will include each individual primary outcome as well as acute SCAD extension and quality of life/Seattle Angina Score in prospectively recruited participants. Endpoints will be assessed at the end of the hospital admission and at 30-days, 1 year, and median long-term follow-up.Multicentre ethics approval has been granted from the Western Sydney Local Health District Human Research Ethics Committee (2021/ETH00040).The analysed results will be published in peer-reviewed journals on completion of the historical data collection and then on completion of the prospective data collection.The ANZ-SCAD registry has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621000824864).

Background: Twenty percent to 40% of patients are affected by angina after percutaneous coronary intervention (PCI), which is associated with anxiety, depression, impaired physical function, and reduced quality of life. Understanding patient and procedural factors associated with post-PCI angina may inform alternative approaches to treatment. Methods: Two hundred thirty patients undergoing PCI completed the Seattle Angina Questionnaire (SAQ-7) and European quality of life–5 dimension–5 level (EQ-5D-5L) questionnaires at baseline and 3 months post-PCI. Patients received blinded intracoronary physiology assessments before and after stenting. A post hoc analysis was performed to compare clinical and procedural characteristics among patients with and without post-PCI angina (defined by follow-up SAQ-angina frequency score Results: Eighty-eight of 230 patients (38.3%) reported angina 3 months post-PCI and had a higher incidence of active smoking, atrial fibrillation, and history of previous myocardial infarction or PCI. Compared with patients with no angina at follow-up, they had lower baseline SAQ summary scores (69.48±24.12 versus 50.20±22.59, P P P =0.003). Percentage change in FFR after PCI had a moderate correlation with angina frequency score at follow-up ( r =0.36, P P P ≤0.001) and EQ-5D-5L index scores (0.69±0.26 versus 0.91±0.17, P ≤0.001) at follow-up. Conclusions: Larger improvements in FFR following PCI were associated with less angina and better quality of life at follow-up. In patients with stable symptoms, intracoronary physiology assessment can inform expectations of angina relief and quality of life improvement after stenting and thereby help to determine the appropriateness of PCI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03259815.

Aims To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). Methods and results The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365–744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). Conclusions This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis., Graphical Abstract

Coronary perforation is a potentially life-threatening complication of percutaneous coronary intervention (PCI). We studied incidence, outcomes and temporal trends following PCI-related coronary artery perforation (CAP).MethodsProspective systematic review and meta-analysis including meta-regression using MEDLINE and EMBASE to November 2020. We included ‘all-comer’ PCI cohorts including large PCI registries and randomised controlled trials and excluding registries or trials limited to PCI in high-risk populations such as chronic total occlusion PCI or cohorts treated only with atheroablative devices. Regression analysis and corresponding correlation coefficients were performed comparing perforation incidence, mortality rate, tamponade rate and the rate of Ellis III perforations against the midpoint (year) of data collection to determine if a significant temporal relationship was present.Results3997 studies were screened for inclusion. 67 studies met eligibility criteria with a total of 5 568 191 PCIs included over a 38-year period (1982–2020). The overall pooled incidence of perforation was 0.39% (95% CI 0.34% to 0.45%) and remained similar throughout the study period. Around 1 in 5 coronary perforations led to tamponade (21.1%). Ellis III perforations are increasing in frequency and account for 43% of all perforations. Perforation mortality has trended lower over the years (7.5%; 95% CI 6.7% to 8.4%). Perforation risk factors derived using meta-regression were female sex, hypertension, chronic kidney disease and previous coronary bypass grafting. Coronary perforation was most frequently caused by distal wire exit (37%) followed by balloon dilation catheters (28%). Covered stents were used to treat 25% of perforations, with emergency cardiac surgery needed in 17%.ConclusionCoronary perforation complicates approximately 1 in 250 PCIs. Ellis III perforations are increasing in incidence although it is unclear whether this is due to reporting bias. Despite this, the overall perforation mortality rate (7.5%) has trended lower in recent years. Limitations of our findings include bias that may be introduced through analysis of multidesign studies and registries without pre-specified standardised perforation reporting CMore research into coronary perforation management including the optimal use of covered stents seems warranted.PROSPERO registration numberCRD42020207881.

BACKGROUND Intravascular lithotripsy (IVL) is a novel alternative to rotational atherectomy (RA) for the modification of heavily calcified coronary stenoses prior to percutaneous coronary intervention (PCI). We compare the real-world resource utilisation and associated costs of PCI with adjunctive RA and IVL. METHODS We compared the resource utilisation, in-lab consumable costs and procedural data of 120 patients who underwent PCI with IVL from the Disrupt-CAD II study (NCT03328949) to 60 patients who underwent PCI with RA at the Golden Jubilee National Hospital, Glasgow. The RA patients were consecutive and selected on the basis of being deemed suitable for IVL by an independent interventional cardiologist experienced in the use of both techniques. RESULTS PCI with IVL was associated with significantly lower costs than PCI with RA (mean difference £398 [95% CI, £181-£615]; p

Background Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. Methods We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. Conclusion PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care.

Background 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 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., Graphical abstract Unlabelled Image

IntroductionThere is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75–0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia inGZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control.MethodsWe enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ).Results104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the targetGZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months.ConclusionsNon-invasive evidence of major ischaemia is uncommon in patients withGZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months.Trial registration numberNCT02425969.

Objectives The aim of this study was to test the hypothesis that invasive coronary function testing at time of angiography could help stratify management of angina patients without obstructive coronary artery disease. Background Medical therapy for angina guided by invasive coronary vascular function testing holds promise, but the longer-term effects on quality of life and clinical events are unknown among patients without obstructive disease. Methods A total of 151 patients with angina with symptoms and/or signs of ischemia and no obstructive coronary artery disease were randomized to stratified medical therapy guided by an interventional diagnostic procedure versus standard care (control group with blinded interventional diagnostic procedure results). The interventional diagnostic procedure–facilitated diagnosis (microvascular angina, vasospastic angina, both, or neither) was linked to guideline-based management. Pre-specified endpoints included 1-year patient-reported outcome measures (Seattle Angina Questionnaire, quality of life [EQ-5D]) and major adverse cardiac events (all-cause mortality, myocardial infarction, unstable angina hospitalization or revascularization, heart failure hospitalization, and cerebrovascular event) at subsequent follow-up. Results Between November 2016 and December 2017, 151 patients with ischemia and no obstructive coronary artery disease were randomized (n = 75 to the intervention group, n = 76 to the control group). At 1 year, overall angina (Seattle Angina Questionnaire summary score) improved in the intervention group by 27% (difference 13.6 units; 95% confidence interval: 7.3 to 19.9; p, Central Illustration

Background Coronary vasospasm is an increasingly recognized cause of myocardial infarction or myocardial ischaemia in patients without obstructive coronary artery disease. A thorough medication review may identify drugs or toxins that could trigger coronary vasospasm. This case provides mechanistic insight into the off-target effect of proteasome inhibition leading to coronary vasospasm in a patient referred with chest pain consistent with typical angina. Case summary A 72-year-old lady presented with anginal chest pain at rest with electrocardiogram evidence of myocardial ischaemia who was referred for invasive coronary angiography. This demonstrated minor coronary disease without an obstructive lesion. Vasoreactivity testing revealed diffuse coronary vasospasm of the left anterior descending artery. Carfilzomib was identified as the trigger for coronary vasospasm. Symptoms resolved without recurrence after appropriate treatment including cessation of the triggering agent. Conclusion Coronary spasm is a rare but important adverse reaction to proteasome inhibitors. This case supports the clinical utility of invasive coronary vasoreactivity testing in patients with ischaemia with no obstructive coronary artery disease.

Aims A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. Methods and results After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR Conclusion Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

Patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (INOCA) present a diagnostic and therapeutic challenge. Microvascular and/or vasospastic angina are the two most common causes of INOCA; however, invasive coronary angiography lacks the sensitivity to diagnose these functional coronary disorders. In this article, the authors summarise the rationale for invasive testing in the absence of obstructive coronary disease, namely that correct treatment for angina patients starts with the correct diagnosis. They provide insights from the CORonary MICrovascular Angina (CorMicA) study, where an interventional diagnostic procedure was performed with linked medical therapy to improve patient health. Identification of these distinct disorders (microvascular angina, vasospastic angina or non-cardiac chest pain) is key for stratifying INOCA patients, allowing prognostic insights and better patient care with linked therapy based on contemporary guidelines. Finally, they propose a framework to diagnose and manage patients in this common clinical scenario.

Background: Patients with angina symptoms and/or signs of ischemia but no obstructive coronary artery disease (INOCA) pose a diagnostic and therapeutic challenge.Objectives: The purpose of ...

Aim Coronary angiography is indicated in many patients with known or suspected angina for the investigation of coronary artery disease (CAD). However, up to half of patients with symptoms of ischaemia have no obstructive coronary arteries (INOCA). This large subgroup includes patients with suspected microvascular angina (MVA) and/or vasospastic angina (VSA). Clinical guidelines relating to the management of patients with INOCA are limited. Uncertainty regarding the diagnosis of patients with INOCA presents a health economic challenge, both in terms of healthcare resource utilisation and of quality-of-life impact on patients. Methods A cost-effectiveness analysis of the introduction of stratified medicine into the invasive management of INOCA, based on clinical and resource-use data obtained in the CorMicA trial, from a UK NHS perspective. The intervention included an invasive diagnostic procedure (IDP) of coronary vascular function during coronary angiography to define clinical endotypes to target with linked medical therapy. Outcomes of interest were mean total cost and QALY gain between treatment groups, and the incremental cost-effectiveness ratio. We undertook probabilistic sensitivity and scenario analyses. Results The incremental cost per QALY gained at 12 months was £4500 (£2937, £33264). Compared with a willingness-to-pay (WTP) threshold of £20,000 per QALY, the use of the IDP test is cost-effective. At this WTP threshold there is a 96% probability of the IDP being cost-effective, based on the uncertainty described by bootstrap analysis. Conclusions The burden of INOCA, particularly in women, is known to be significant. These findings provided new evidence to inform this unmet clinical need.

Background: The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. Methods: IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. Results: IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17–55), the median LVEDP was 17 mm Hg (interquartile range, 12–21), and the correlation between them was not statistically significant ( r =0.15; P =0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P =0.045) and major adverse cardiac events (n=21 events; P =0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60–21.22] P =0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7–98.2; P =0.033) when LVEDP>18 was added to IMR>32. Conclusions: IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02257294.

A man in his 60s presented to the emergency department with two hours of gradually worsening right-sided chest pain that occurred at rest. During the week before presentation he had also experienced a coryzal illness, including rhinorrhoea, non-productive cough, fever, and lethargy. He described shorter episodes of chest pain, lasting less than 15 minutes, for four weeks before this attendance, but he had not sought medical advice. His vital signs were stable, he was apyrexial, and had normal heart sounds and no pericardial rub. His right chest wall was tender to palpation, particularly at the costochondral margins. The patient was a smoker, had a history of hypertension and dyslipidaemia, and a family history of angina. …

Background Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. Objective To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. Design This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. Setting The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. Participants Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. Intervention A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. Outcomes The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. Sample size A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was Methods The primary outcome was compared between groups using a stratified Wilcoxon rank-sum test (van Elteren test), stratified by the location of the myocardial infarction. Results Among the 440 patients (mean age of 60.5 years; 15% women), the primary end point was measured in 396 (90%) patients, 17 (3.9%) withdrew, seven died and all other patients were followed up to 3 months. The amount (mean percentage of left ventricular mass) of microvascular obstruction was 2.3% versus 2.6% versus 3.5% in the placebo, 10 mg of alteplase and 20 mg of alteplase groups, respectively. In the primary analysis, microvascular obstruction did not differ between the 20 mg of alteplase group and the placebo group: 3.5% versus 2.3%, estimated difference 1.16% (95% confidence interval –0.08% to 2.41%; p = 0.32). In the secondary analysis, microvascular obstruction did not differ between the 10 mg of alteplase group and the placebo group: 2.6% versus 2.3%, estimated difference 0.29% (95% confidence interval –0.76% to 1.35%; p = 0.74). By 3 months, major adverse cardiac events (cardiac death, non-fatal myocardial infarction and unplanned hospitalisation for heart failure) had occurred in 15 (10.1%) patients in the placebo group, 18 (12.9%) in the 10 mg of alteplase group and 12 (8.2%) in the 20 mg of alteplase group. Conclusions Adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction compared with placebo. Limitations Premature discontinuation of enrolment limited the power of the secondary and safety analyses. Future work Low-dose intracoronary alteplase or tenecteplase could be compared with placebo at the end of primary percutaneous coronary intervention in patients with an ischaemic time of Trial registration This trial is registered as ClinicalTrials.gov NCT02257294. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 5. See the NIHR Journals Library website for further project information.

Background Angina is associated with impaired quality of life and an adverse prognosis. Purpose Prospectively evaluate quality of life and clinical outcomes in patients with angina undergoing invasive coronary angiography according to endotype: symptoms and/or signs of ischaemia and no obstructive coronary artery disease (INOCA) compared to obstructive coronary artery disease subjects managed by medical therapy, revascularization with percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery, respectively. Methods We conducted a prospective clinical evaluation of patients with angina undergoing clinically indicated invasive management (NCT03193294). Symptom severity and quality of life were assessed at baseline and repeated after 6 months. Comparisons between treatment groups were based on analysis of covariance general linear models adjusting for baseline score, sex, and cardiovascular risk. INOCA subjects were considered as one diagnostic group and not all subjects had invasive vasoreactivity testing. Results 391 patients (mean age 62±10 years, 52% female) were enrolled over 12 months and classified into one of four groups: INOCA (N=185; 47%), obstructive CAD treated by PCI (N=126; 32%), obstructive CAD treated by CABG (N=48; 12%) and obstructive CAD managed with medical therapy (N=32; 8%). After adjusting for between group differences and overall risk, INOCA subjects had worse angina and worse treatment response at follow up (21% and 27% reduction in angina score compared to CAD patients revascularized with PCI and CABG respectively). INOCA subjects had numerically lower treatment response than CAD patients managed with medications (6.4 units, −12%; P=0.181). Population baseline mean Seattle Angina Questionnaire (SAQ) frequency score (60±26) and SAQ summary score (52.5±19) were similar between groups. The absolute difference was 6.4 units versus medically managed CAD (95% CI: −3.0 to 15.9; P=0.181), 11.3 units versus the CAD group undergoing PCI (6.1 to 16.5; P Conclusion(s) Patients with INOCA had more severe angina symptoms reflecting worse quality of life and treatment response at 6 months with similar MACE as CAD subjects even after adjustment for confounding factors. This study highlights the need for evidence-based antianginal therapies and disease-modifying treatments for angina patients regardless of the presence of obstructive coronary disease. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was funded by the British Heart Foundation (PG/17/2532884; RE/13/5/30177; RE/18/6134217)

Aims Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). Methods and results Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10–0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; −3.0 units in Duke Exercise Treadmill Score; −5.8 to −0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. Conclusion We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. Trial registration ClinicalTrials.gov: NCT03193294.

No abstract available.

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care., Central Illustration, Highlights • Patients with symptoms of INOCA can have treatable coronary vasomotion disorders. • Epicardial and microvascular vasospasm may cause MI with no obstructive CAD and type 2 MI. • Invasive physiological testing (functional coronary angiography) helps exclude, diagnose, and treat these conditions. • Stratified medicine can transform the management and well-being of these patients.

Supplemental Digital Content is available in the text., Background: Determine the prevalence and correlates of microvascular and vasospastic angina in patients with symptoms and signs of ischemia but no obstructive coronary artery disease (INOCA). Methods: Three hundred ninety-one patients with angina were enrolled at 2 regional centers over 12 months from November 2016 (NCT03193294). INOCA subjects (n=185; 47%) had more limiting dyspnea (New York Heart Association classification III/IV 54% versus 37%; odds ratio [OR], 2.0 [1.3–3.0]; P=0.001) and were more likely to be female (68% INOCA versus 38% in coronary artery disease; OR, 1.9 [1.5 to 2.5]; P

Background Adenosine is frequently used during coronary angiography to induce hyperaemia and allow operators to perform quantitative measurements of lesion severity. Acute bronchospasm is a recognised side effect relating to the activation of ‘off target’ A2B receptors. The true incidence of severe bronchospasm relating to adenosine administration is not known. Methods Using an electronic patient database, we analysed 100,253 consecutive coronary angiograms over almost 19 years. Fractional flow reserve (FFR) was measured under systemic adenosine in 9,440 cases. Results Adenosine-related bronchospasm was reported in only five cases (0.05%). One case resulted in a life-threatening respiratory arrest. Conclusions This study reveals the incidence of acute bronchospasm during FFR testing to be extremely low. Although rare, these reactions can be severe and are not simply limited to patients with brittle airways disease. Physicians should be aware of the utility of bolus intravenous aminophylline providing targeted therapy to reverse and treat adenosine-related bronchospasm.

Background Heart failure (HF) is a major cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) now accounts for around half of the HF population. To date, no treatments for HFpEF have proven effect and outcomes have not improved in recent decades. The heterogeneity of the HFpEF population and the failure of randomised controlled trials (RCTs) to demonstrate effective therapies has led to attempts to identify sub-phenotypes of HFpEF which may respond to targeted therapies. Recent studies suggest that epicardial coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may play an important role in a substantial group of patients with HFpEF. A novel paradigm has been proposed suggesting that endothelium-dependent CMD may play a key role in the unifying pathophysiology of HFpEF. I performed a systematic review of the literature describing the prevalence of epicardial CAD and CMD in HFpEF populations. Most studies were retrospective observational and population-based studies with inconsistent definitions of HF, preserved left ventricular ejection fraction (LVEF) and CAD. Studies which documented CAD angiographically were almost exclusively performed in highly-selected convenience cohorts. Consequently, prevalence estimates of CAD in HFpEF varied considerably between studies. Similarly, studies assessing CMD in HFpEF reported inconsistent results due to variable definitions of CMD and methods of assessing coronary microvascular function. Therefore, the prevalence of epicardial CAD and CMD have not been prospectively and systematically studied in an unselected HFpEF population. Aims The main aims of this study were to determine the prevalence of obstructive epicardial CAD, CMD and previous myocardial infarction (MI) in an unselected cohort of patients hospitalised with HFpEF using reference standard invasive investigations. Methods This was a prospective, multicentre, observational study of patients hospitalised with HFpEF. All patients recruited had a confirmed diagnosis of HFpEF according to the 2016 European Society of Cardiology (ESC) HF guidelines. Participants underwent invasive coronary angiography with guidewire-based assessment of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), followed by vasoreactivity testing with intra-coronary acetylcholine. This allowed the comprehensive assessment of epicardial and microvascular structure and function to determine the prevalence of CAD, CMD and coronary endothelial dysfunction in the cohort. Adenosine perfusion cardiac magnetic resonance (CMR) imaging was also performed to assess the burden of myocardial infarction (MI), diffuse fibrosis and inducible ischaemia in the study population. Patients were followed up by electronic medical record linkage for a minimum of 12 months. Results Of 2285 near-consecutive patients hospitalised with suspected HF, 628 were confirmed to have a diagnosis of HFpEF, and 106 HFpEF patients met the inclusion criteria and agreed to participate in the study. A total of 83 participants underwent invasive coronary angiography or CMR. Seventy-five participants underwent invasive coronary angiography, 62 had guidewire-based coronary physiology testing, and 41 underwent vasoreactivity testing. Fifty-two participants underwent CMR and 44 had both invasive coronary angiography and CMR. Twenty-three patients did not proceed to the study investigations, predominantly due to a decline in health, functional status or renal function making proceeding with the study investigations inappropriate or unsafe. In this unselected hospitalised HFpEF cohort, the prevalence of obstructive epicardial CAD on invasive assessment was 51% (95% confidence interval [CI] 39-62%); half of patients with obstructive epicardial disease had no clinical history of CAD. On invasive coronary physiological testing, 41 patients (66% [95% CI 53-77%]) had endothelium-independent CMD, and 10 (24% [95% CI 13-40%]) had endothelium-dependent CMD. Overall, 91% of participants had evidence of macrovascular and/or microvascular CAD. Of those who underwent CMR, 27% (95% CI 16-41%) had evidence of previous MI and 32% (95% CI 19-48%) had inducible ischaemia. Over half of patients with CMR-proven MI had no history of clinically apparent MI. Over a median follow-up period of 18 months, study participants with obstructive epicardial CAD had significantly more hospitalisations (for any cause, a cardiovascular cause or HF) than those without obstructive CAD. There was no significant difference in outcomes between those with or without endothelium-independent or -dependent CMD. Conclusion Both epicardial CAD and CMD are common in the HFpEF population, and there is a high prevalence of clinically unrecognised obstructive epicardial CAD and previous MI. Patients with obstructive epicardial CAD had significantly more hospitalisations than those without obstructive disease. Treatments for epicardial CAD (e.g. coronary revascularisation) might improve quality of life and reduce hospitalisations in HFpEF patients with CAD. Although it has been hypothesised that CMD in HFpEF is the result of endothelial dysfunction, it appears to be predominantly due to endothelium-independent mechanisms. This may have important implications for future treatments directed at CMD in patients with HFpEF.

Objectives The aim of this study was to quantify the radiation dose reduction during coronary angiography and percutaneous coronary intervention (PCI) through removal of the anti-scatter grid (ASG), and to assess its impact on image quality in adult patients with a low body mass index (BMI). Methods A phantom with different thicknesses of acrylic was used with a Westmead Test Object to simulate patient sizes and assess image quality. 129 low BMI patients underwent coronary angiography or PCI with or without the ASG in situ. Radiation dose was compared between both patient groups. Results With the same imaging system and a comparable patient population, ASG removal was associated with a 47% reduction in total dose-area product (DAP) (p

We applaud Liu et al. [(1)][1] for their stimulating paper, “Diagnosis of Microvascular Angina Using Cardiac Magnetic Resonance.” Coronary microvascular dysfunction (CMD) was defined as an index of microcirculatory resistance (IMR) ≥25 measured in an epicardial vessel without flow-limiting