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Aims: \ud Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevated myocardial infarction (STEMI) to heart failure. Here we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.\ud \ud Methods and Results: \ud We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 hour post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies, demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.\ud \ud Conclusion: \ud Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.\ud \ud Translational perspective: \ud New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.

Background Segmental extent of infarction assessed by late gadolinium enhancement (LGE) imaging early post‐ST‐segment elevation myocardial infarction (STEMI) has utility in predicting left ventricular functional recovery. Hypothesis: We hypothesized that segmental circumferential strain with displacement encoding with stimulated echoes (DENSE) would be a stronger predictor of infarct transmurality than feature‐tracking strain, and noninferior to extracellular volume fraction (ECV). Study Type: Prospective. Population: Fifty participants (mean ± SD, 59 ± 9 years, 40 [80%] male) underwent cardiac MRI on day 1 post‐STEMI. Field‐Strength/Sequences: 1.5T/cine, DENSE , T1 mapping, ECV , LGE. Assessment Two observers assessed segmental percentage LGE extent, presence of microvascular obstruction (MVO), circumferential and radial strain with DENSE and feature‐tracking, T1 relaxation times, and ECV. Statistical Tests: Normality was tested using the Shapiro–Wilk test. Skewed distributions were analyzed utilizing Mann–Whitney or Kruskal–Wallis tests and normal distributed data using independent t ‐tests. Diagnostic cutoff values were identified using the Youden index. The difference in area under the curve was compared using the z‐statistic. Results: Segmental circumferential strain with DENSE was associated with the extent of infarction ≥50% (AUC [95% CI], cutoff value = 0.9 [0.8, 0.9], −10%) similar to ECV (AUC = 0.8 [0.8, 0.9], 37%) (P = 0.117) and superior to feature‐tracking circumferential strain (AUC = 0.7[0.7, 0.8], −19%) (P

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

BackgroundCoronary 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).MethodsACS 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.ResultsOf 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.ConclusionsCompared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar.Trial registration numberNCT01895751.

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.

Objectives: To describe outcomes following percutaneous coronary intervention (PCI) in patients who would usually have undergone coronary artery bypass grafting (CABG). Background: In the United Kingdom, cardiac surgery for coronary artery disease (CAD) was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with “surgical disease” instead underwent PCI. Methods: Between 1 March 2020 and 31 July 2020, 215 patients with recognized “surgical” CAD who underwent PCI were enrolled in the prospective UK-ReVasc Registry (ReVR). 30-day major cardiovascular event outcomes were collected. Findings in ReVR patients were directly compared to reference PCI and isolated CABG pre-COVID-19 data from British Cardiovascular Intervention Society (BCIS) and National Cardiac Audit Programme (NCAP) databases. Results: ReVR patients had higher incidence of diabetes (34.4% vs 26.4%, P =.008), multi-vessel disease with left main stem disease (51.4% vs 3.0%, P

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.

Intravascular lithotripsy (IVL) has been shown to be safe and effective for calcium modification in nonocclusive coronary artery disease (CAD), but there are only case reports of its use in calcified chronic total occlusions (CTO). We report data from an international multicenter registry of IVL use during CTO percutaneous coronary intervention (PCI) and provide provisional data regarding its efficacy and safety. During the study period, IVL was used in 55 of 1053 (5.2%) CTO PCI procedures. IVL was used within the occluded segment after successful CTO crossing in 53 procedures and during incomplete CTO crossing in 2 cases. The mean J-CTO score was 3.1. CTO PCI technical and procedural success was achieved in 53 (96%) and 51 (93%) cases. Six patients had a procedural complication, with 3 main vessel perforations (5%). Two had covered stent implantation, one required pericardiocentesis, and one was managed conservatively. All had combination therapy with another calcium modification device. Two patients had a procedural myocardial infarction (PMI) (4%), and two others had a major adverse cardiovascular event (MACE) (4%) at a median follow-up of 13 (4–21) months. IVL can effectively facilitate calcium modification during CTO PCI. More data are required to establish the efficacy and safety of IVL and other calcium modification devices when used extraplaque or in combination during CTO PCI.

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)

Supplemental Digital Content is available in the text., Background: The resistive reserve ratio (RRR) expresses the ratio between basal and hyperemic microvascular resistance. RRR measures the vasodilatory capacity of the microcirculation. We compared RRR, index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) for predicting microvascular obstruction (MVO), myocardial hemorrhage, infarct size, and clinical outcomes, after ST-segment–elevation myocardial infarction. Methods: In the T-TIME trial (Trial of Low-Dose Adjunctive Alteplase During Primary PCI), 440 patients with acute ST-segment–elevation myocardial infarction from 11 UK hospitals were prospectively enrolled. In a subset of 144 patients, IMR, CFR, and RRR were measured post-primary percutaneous coronary intervention. MVO extent (% left ventricular mass) was determined by cardiovascular magnetic resonance imaging at 2 to 7 days. Infarct size was determined at 3 months. One-year major adverse cardiac events, heart failure hospitalizations, and all-cause death/heart failure hospitalizations were assessed. Results: In these 144 patients (mean age, 59±11 years, 80% male), median IMR was 29.5 (interquartile range: 17.0–55.0), CFR was 1.4 (1.1–2.0), and RRR was 1.7 (1.3–2.3). MVO occurred in 41% of patients. IMR>40 was multivariably associated with more MVO (coefficient, 0.53 [95% CI, 0.05–1.02]; P=0.031), myocardial hemorrhage presence (odds ratio [OR], 3.20 [95% CI, 1.25–8.24]; P=0.016), and infarct size (coefficient, 5.05 [95% CI, 0.84–9.26]; P=0.019), independently of CFR≤2.0, RRR≤1.7, myocardial perfusion grade≤1, and Thrombolysis in Myocardial Infarction frame count. RRR was multivariably associated with MVO extent (coefficient, −0.60 [95% CI, −0.97 to −0.23]; P=0.002), myocardial hemorrhage presence (OR, 0.34 [95% CI, 0.15–0.75]; P=0.008), and infarct size (coefficient, −3.41 [95% CI, −6.76 to −0.06]; P=0.046). IMR>40 was associated with heart failure hospitalization (OR, 5.34 [95% CI, 1.80–15.81] P=0.002), major adverse cardiac events (OR, 4.46 [95% CI, 1.70–11.70] P=0.002), and all-cause death/heart failure hospitalization (OR, 4.08 [95% CI, 1.55–10.79] P=0.005). RRR was associated with heart failure hospitalization (OR, 0.44 [95% CI, 0.19–0.99] P=0.047). CFR was not associated with infarct characteristics or clinical outcomes. Conclusions: In acute ST-segment–elevationl infarction, IMR and RRR, but not CFR, were associated with MVO, myocardial hemorrhage, infarct size, and clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02257294.

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.

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST ‐segment–elevation myocardial infarction. In the T‐ TIME (A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T‐ TIME trial. From 2016 to 2017, patients with ST ‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (P =0.013), resistive reserve ratio ( P =0.026), and microvascular obstruction ( P =0.022), but not index of microcirculatory resistance. Conclusions In ST ‐segment–elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02257294.

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 Chronic total occlusion (CTO) revascularisation has a crucial role in contemporary percutaneous coronary intervention (PCI). Procedural success is influenced by disease complexity, calcific burden and patient characteristics but has substantially improved with the implementation of novel hybrid strategies. However, vascular-access related complications remain a cause of morbidity and mortality. This study aimed to assess the effectiveness of fluoroscopic-guided femoral arterial puncture to minimise this risk during CTO PCI. Methods Standardised data were retrospectively collected from four high-volume UK CTO centres between September 2011 and November 2013. Demographic, clinical and procedural data (vascular access site, sheath size, anticoagulation use) was collated. The anatomical location of the femoral puncture in relation to the femoral bifurcation, femoral head position and inferior epigastric artery were recorded. Adverse events related to vascular access were documented. Results A total of 528 patients were included (676 femoral punctures) with the majority being male (n=432, 81.8%). Large sheaths (8F) were used in 81.2% of cases. Fluoroscopy-enabled punctures were made in the ‘safe zone’ in over > 93% of cases. Vascular closure devices (VCD) were used in 88.3% of cases. The adverse event rate per puncture was 0.89%. Conclusions This study demonstrates an extremely low incidence of vascular-access complications in CTO PCI when fluoroscopic guidance is used to obtain femoral arterial access by default radial operators.

Background Impaired microcirculatory reperfusion worsens prognosis post-primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Intracoronary (IC) alteplase targets persisting thrombus post-reperfusion & distal embolisation. In the T-TIME trial microvascular obstruction on cardiac magnetic resonance (CMR) did not differ with IC alteplase vs placebo. Purpose To prospectively determine if index of microcirculatory resistance (IMR) is lower & coronary flow reserve (CFR) or resistive reserve ratio (RRR) are higher (improved) with IC alteplase, & to provide mechanistic insights. Methods A pre-planned substudy of the main protocol. From 2016–2017, STEMI patients from 3 UK hospitals ≤6 hrs ischaemic time were randomised in a 1:1:1 dose-ranging, double-blind design. Following standard care reperfusion, alteplase (10 or 20mg) or placebo was infused over 5–10 mins proximal to the culprit lesion pre-stenting. IMR (primary outcome), CFR & RRR (secondary outcomes) were measured in the culprit artery post-PCI. Physiology results were obscured from clinicians acquiring the data, to maintain blinding. CMR was performed 2 days & 3 months post-STEMI. Subgroup analyses were prespecified including by ischaemic time (4 hrs) & IMR threshold >32. Results In 144 patients (mean age 59 yrs, 80% male), IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo (Table). Patients with ischaemic time 32, % ST-resolution at 60 mins was worse with alteplase 10mg vs placebo (23.1±53.9 vs 50.9±31.5) & in those with IMR≤32% ST-resolution at 60 mins was better with alteplase 20mg vs placebo (68.0±30.7 vs 39.1±43.2), p=0.002 for interaction. The CMR findings in the substudy & overall trial populations were consistent. Main results Placebo Alteplase 10mg Alteplase 20mg (n=53) (n=41) (n=50) IMR, median (IQR) 33.0 (17.0–57.0) 22.0 (17.0–42.0) 37.0 (20.0–57.8) p=0.15 p=0.78 CFR, median (IQR) 1.3 (1.1–1.8) 1.4 (1.1–1.9) 1.5 (1.1–2.0) p=0.92 p=0.74 RRR, median (IQR) 1.6 (1.3–2.2) 1.6 (1.4–2.6) 1.8 (1.3–2.4) p=0.69 p=0.81 P-values for comparison of alteplase with placebo. Conclusions In acute STEMI with ischaemic time ≤6 hrs, IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo. In those with shorter ischaemic times ( Acknowledgement/Funding Dr Maznyczka is funded by a fellowship from the British Heart Foundation (FS/16/74/32573). T-TIME was funded by grant 12/170/4 from NIHR-EME

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.

Background Ischemia and no obstructive epicardial coronary artery disease (INOCA) is a common clinical syndrome with distinct underlying causes. Objective To evaluate the prevalence and predictors of microvascular and/or vasospastic angina (MVA/VSA) in an unselected cohort of angina patients referred for invasive coronary angiography with suspected ischaemic heart disease in whom obstructive coronary artery disease (CAD) is excluded. Methods Prospective cohort study at two regional centres between November 2016 and December 2017 including patients with symptoms and/or signs of ischaemia prior to undergoing invasive coronary angiography (NCT03193294). Baseline risk was assessed (ASSIGN score) and validated questionnaires were completed prior to the angiogram including Rose angina, quality of life (EuroQOL [EQ-5D-5L]) and angina severity according to the Seattle Angina Questionnaire (SAQ). Patients with definite or probable angina without CAD [diameter stenosis 0.80] proceeded directly to assessment for disorders of coronary vasomotion. This involved an ad hoc interventional diagnostic procedure (IDP) using reference invasive tests for microvascular angina (MVA), vasospastic angina (VSA), both conditions or none. MVA and VSA groups were compared before logistic regression was performed to assess predictors of MVA and VSA. Results Three hundred and ninety-one patients with angina were recruited before undergoing invasive coronary angiography during the study period. Overall, 185 (47%) of subjects had INOCA and 151 of these underwent an IDP. INOCA patients reported similar angina burden with worse quality of life than CAD subjects (EQ5D-5L index 0.60 v 0.65 units; P=0.041). The mean age of patients who underwent the IDP was 60.9 years, 74% were female and their median predicted 10-year IHD risk was 18.6% (10.6, 31.4). 78 subjects (52%) had isolated microvascular angina, 25 (17%) had isolated vasospastic angina, 31 (20%) had both (MVA & VSA) only 17 (11%) had non-cardiac chest pain. Myocardial bridging of coronary artery was found in 22 (15%). Multivariate predictors of MVA included typical angina, inducible ischaemia but traditional cardiovascular risk factors were not associated. Smoking and age were independent predictors of VSA. Conclusion The majority of patients with symptoms and/or signs of ischemia and no obstructive disease have a diagnosis of microvascular and/or vasospastic angina. Traditional cardiovascular risk scores have limited discrimination for disorders of coronary vasomotion. Conflict of Interest Nil

Aims Despite advances in understanding the physiological role of collaterals in coronary chronic total occlusions (CTOs), collateral anatomy remains poorly defined. Our aim was to define the anatomy and interventional utility of collaterals within a large population of patients with CTOs. Methods and results We studied the coronary angiograms of 481 patients with 519 CTOs at six centres in the U.K. over four years. Detailed angiographic analysis was performed by interventional cardiologists specialising in CTO percutaneous coronary intervention (PCI). All visible collaterals with a collateral connection (CC) grade ≥1 were recorded. A subgroup of CTOs (n=277) was assessed for interventional capability, defined as whether the collateral supply was able to facilitate retrograde access. We described 45 different collateral patterns: 20 in right coronary artery (RCA), 13 in left anterior descending (LAD), and 12 in circumflex artery CTOs. Septal collaterals from the LAD to the right posterior descending artery (RPDA), and from the posterior descending artery to the LAD were most common, and most often considered as having "interventional capability". Conclusions This is the largest analysis of collateral circulation anatomy in a population of patients with CTOs. We anticipate that these data will be of significant benefit in angiographic analysis and procedure planning for CTO PCI.

Background Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent ischaemia in a tissue remote from the heart. Its mechanisms are incompletely understood. We hypothesised that RIPC might enhance coronary vasodilatation by an endothelium-dependent mechanism. Methods We performed a prospective, randomised, sham-controlled, blinded clinical trial. Patients with stable coronary artery disease undergoing elective angiography were randomised 1:1 to RIPC or sham. Endothelial-dependent and –independent function was assessed with intracoronary (ic) acetylcholine (ACh) and ic nitrate, respectively. Coronary luminal diameter was assessed by QCA. Primary outcome: between-group difference in mean% change in coronary luminal diameter following ACh. Results Following angiography, 60/75 patients (mean ±SD age 57.5±8.5 years; 80% male) were eligible and completed the protocol (n=30 RIPC, n=30 sham). The mean% change in coronary luminal diameter was −13.3±22.3% and −2.0±17.2% in the sham and RIPC groups respectively (difference 11.32%, 95% CI: 1.2 to 21.4, p=0.032) (figure 1). This remained significant with age and sex as covariates (difference 11.01%, 1.01–21.0, p=0.035). Conclusions RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion, and this endothelium-dependent mechanism may contribute to its cardioprotective effects.

Background There is an evidence-gap about how to best treat patients with a history of prior CABG presenting with a NSTE-ACS because these patients were excluded from key randomised trials. Methods The CABG-ACS pilot trial (NCT01895751) randomised patients with a NSTE-ACS and prior CABG to routine invasive or non-invasive management. The primary efficacy outcome was a composite of all-cause death, rehospitalisation for refractory ischaemia/angina, MI and HF hospitalisation. The primary safety outcome was a composite of bleeding, stroke, procedure-related MI and worsening renal function. A CEC assessed events. Results 60 patients (mean ±SD age 71±9 years, 28% female) were randomised to invasive (n=31) or non-invasive (n=29) management. The invasive group had worse NYHA class (p=0.044) and less valve disease (17% vs 27%; p=0.035). Other comorbidities, age, sex, CCS grade, frailty score and medications were similar. Baseline LIMA grafts were similar (p=0.720). All invasive group patients had invasive management (mean BCIS-1 Jeopardy Score 7±4) and 6 (19%) had PCI. 6 non-invasive group patients ended up having invasive management and 3 (50%) had PCI. No patients had redo CABG. The primary efficacy outcome occurred in 42% invasive vs 45% non-invasive groups (RR (95% CI) 0.94 (0.52, 1.67); p=1.000). The primary safety outcome occurred in 26% invasive vs 31% non-invasive groups (RR 0.83 (0.37, 1.86); p=0.777). EQ-5D was similar at 1 year. Conclusion Compared with routine non-invasive management, a strategy of routine invasive management was not associated with patient benefits.

Objective. To evaluate the usefulness of CT scan in Cardiac tumor Design. A descriptive study with convenient sampling Results. We studied seven cases referred to us for work up of cardiac masses, the contrast enhanced CT scan was able to identify and give the extent in five of these patients. Two patients were negative on CT scan but were confirmed to have a mass in the cardiac chamber by echocardiography. While CT was able to identify the thrombotic mass extending into the heart in two of the patients which remained inconclusive on echocardiography. Conclusion. CT is better modality for the extent of the lesion and echocardiography is better as an initial modality to screen the cardiac chambers.

Introduction There is an evidence gap about how to best treat patients with prior coronary artery bypass grafts (CABGs) presenting with non-ST segment elevation acute coronary syndromes (NSTE-ACS) because historically, these patients were excluded from pivotal randomised trials. We aim to undertake a pilot trial of routine non-invasive management versus routine invasive management in patients with NSTE-ACS with prior CABG and optimal medical therapy during routine clinical care. Our trial is a proof-of-concept study for feasibility, safety, potential efficacy and health economic modelling. We hypothesise that a routine invasive approach in patients with NSTE-ACS with prior CABG is not superior to a non-invasive approach with optimal medical therapy. Methods and analysis 60 patients will be enrolled in a randomised clinical trial in 4 hospitals. A screening log will be prospectively completed. Patients not randomised due to lack of eligibility criteria and/or patient or physician preference and who give consent will be included in a registry. We will gather information about screening, enrolment, eligibility, randomisation, patient characteristics and adverse events (including post-discharge). The primary efficacy outcome is the composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction and hospitalisation for heart failure. The primary safety outcome is the composite of bleeding, stroke, procedure-related myocardial infarction and worsening renal function. Health status will be assessed using EuroQol 5 Dimensions (EQ-5D) assessed at baseline and 6 monthly intervals, for at least 18 months. Trial registration number NCT01895751 (ClinicalTrials.gov).

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Background: Elderly patients with multi-morbidity are often under-represented in clinical trials. The CABG-ACS pilot trial (NCT01895751) prospectively assessed reasons for entering the trial or registry and subsequent outcomes. Methods: Patients with a non-ST segment elevation acute coronary syndrome (NSTE-ACS) and prior coronary artery bypass graft (CABG) admitted to 4 hospitals were randomized to invasive or non-invasive management. Non-randomized patients entered a follow-up registry. The primary efficacy outcome was a composite of all-cause death, rehospitalization for refractory ischemia/angina, myocardial infarction (MI) and hospitalization due to heart failure. The primary safety outcome was the composite of bleeding, stroke, procedure-related MI and worsening renal function. A blinded Clinical Event Committee independently assessed events. EuroQol-5 Dimensions (EQ-5D) was assessed at 6 monthly intervals for ≥18 months. Results: 217 patients with prior CABG and unplanned hospitalization for suspected ACS were screened. 84 subjects did not consent (≥1 reasons): 43 not NSTE-ACS, 35 unsuitable for invasive management, 9 refractory ischemia, 3 unable to consent. Of 133 eligible subjects, 60 (mean±SD age 71±9 years, 28% female) entered the trial and 73 (age 72±10 years, 27% female) entered the registry (preferences: physician 79%, patient 40% or both 18%). Compared to trial patients, registry patients had significantly more valve disease, lower hemoglobin, worse New York Heart Association class and higher frailty index. Baseline EQ-5D, medications and left internal mammary artery grafts were similar. Registry patients had significantly more medication changes due to recurrent angina and more urgent inpatient invasive procedures. The primary efficacy outcome occurred in 49% registry vs. 43% trial patients (HR (95% CI) 1.12 (0.77,1.63); p=0.601). Primary safety outcomes were similar (22% registry vs. 28% trial; HR 0.76 (0.42,1.38); p=0.425). EQ-5D health status was lower in the registry at 6 months (p=0.011) but not at 1 year (p=0.068). Conclusion: Compared to trial patients, the registry had excess morbidity but their longer term health outcomes were similar.

OBJECTIVE: To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. METHODS: We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. RESULTS: CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p

Answers 1. ECG No 1 (Figure 1) shows a broad complex irregularly irregular rythum which is consistent with atrial f ibrillation. The ventricular rate is very rapid and there is slow upstroke of R wave in the chest leads indicative of pre-excitation 2. DC Cardioversion is a safe option. In this patient DC Cardioversion was chosen due to the worrying rapid ventricular rate and risk of degeneration into ventricular f ibrillation (VF). Amiodrone in this situation can act as an atrio-ventricular (AV) node blocking agent and lead to unopposed AV conduction and risk of VF. 3. ECG No 2 (Figure 2) shows classical features of pre-excitation with short PR interval and delta wave in leads V2-V6; this is suggestive of the Wolff Parkinson White (WPW) syndrome. 4. Radiofrequency ablation of the accessory pathway is the treatment of choice Picture Quiz Answer: A young man with palpitations

Introduction Myocardial infarction and coronary artery disease in people under 40 years of age are relatively uncommon. To establish a diagnosis, physicians need a high degree of clinical suspicion. Case presentation We report the case of a 33-year-old Caucasian man presenting with classical signs and symptoms of acute pulmonary embolism. Subsequent investigations interestingly revealed right ventricular mural thrombus with no obvious underlying pathology triggering it. On cardiac magnetic resonance imaging, he was found to have a right ventricular infarct with secondary thrombus formation. Coronary angiography confirmed ostial occlusion of the right coronary artery. Conclusion This is an unusual case of premature myocardial infarction presenting primarily with secondary complications.