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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 < 0.001). Quality of life (EQ-5D index) improved in the intervention group relative to the control group (mean difference 0.11 units [18%]; 95% confidence interval: 0.03 to 0.19; p = 0.010). After a median follow-up duration of 19 months (interquartile range: 16 to 22 months), major adverse cardiac events were similar between the groups, occurring in 9 subjects (12%) in the intervention group and 8 (11%) in the control group (p = 0.803). Conclusions Stratified medical therapy in patients with ischemia and no obstructive coronary artery disease leads to marked and sustained angina improvement and better quality of life at 1 year following invasive coronary angiography. (Coronary Microvascular Angina [CorMicA]; NCT03193294 )

(4.6%), VT=1 (0.3%). ANS referrals resulted in greater trend towards change of management (38.2%) of patients compared with GC (32.7%) and EP (31.4%) (p=0.593 nurse vs. consultant). For those needing pacing, 24 were from ANS referrals compared to 25 for clinicians (23.5% vs 18.3% respectively, p=0.012). Median time to developing a pacing indication was 2.6 months for ANS and 4.1 months for clinicians; 25 had pacing indication within 3 months of ILR insertion. Overall, an ILR had a diagnostic yield of 34.1% (n= 104) (table 1). Conclusion The diagnostic yield of ILR insertion was 34%. ANS referrals trended towards greater diagnostic yield compared with clinicians and significantly more pacemaker indications. Our data suggest ANS patient selection for ILRs are at least comparable to clinicians.

BACKGROUND We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). METHODS Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2–6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. RESULTS Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 μmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). CONCLUSION The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

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.

Around 40% of all patients undergoing angiography are found to have normal coronary arteries or non-obstructive coronary artery disease (NOCAD). Despite the high prevalence, this is a group who rarely receive a definitive diagnosis, are frequently labelled and managed inappropriately and by and large, continue to remain symptomatic. Half of this group will have coronary microvascular dysfunction (CMD), associated with a higher rate of major adverse cardiovascular events; identifying CMD represents a therapeutic target of unmet need. As the pressure wire has revolutionised our ability to interrogate epicardial coronary disease during the time of angiography, measuring flow can similarly classify NOCAD during a single procedure. Assessment of flow is a function that is already integral to some pressure wires and furthermore, the familiarity and usage of the combined Doppler and pressure wire is rapidly increasing—these are techniques that readily lend themselves to the skillset of a practising interventional cardiologist. We present a structured algorithm designed for cardiologists who frequently encounter NOCAD in the catheter laboratory, identifying specific disease phenotypes within this heterogeneous population with linked therapy. This review paper clearly explains the rationale for this algorithm and outlines its applicability to routine clinical practice and also, the importance of phenotyping for future research. Ultimately, personalised therapy could improve outcomes for both patients and healthcare providers; while these approaches in turn will need robust evaluation to ensure that they improve both clinical outcomes and health economic benefits, this proposal will provide a framework for future trials and evaluations.

Background: Extremely preterm babies (delivered at <28 completed weeks of gestation) are frequently diagnosed with hypotension and treated with inotropic and pressor drugs in the immediate postnatal period. Dopamine is the most commonly used first-line drug. Babies who are treated for hypotension more frequently sustain brain injury, have long-term disability or die compared to those who are not. Despite the widespread use of drugs to treat hypotension in such infants, evidence for efficacy is lacking, and the effect of these agents on long-term outcomes is unknown. Hypothesis: In extremely preterm babies, restricting the use of dopamine when mean blood pressure (BP) values fall below a nominal threshold and using clinical criteria to determine escalation of support (‘restricted' approach) will result in improved neonatal and longer-term developmental outcomes. Research Plan: In an international multi-centre randomised trial, 830 infants born at <28 weeks of gestation, and within 72 h of birth, will be allocated to 1 of 2 alternative treatment options (dopamine vs. restricted approach) to determine the better strategy for the management of BP, using a conventional threshold to commence treatment. The first co-primary outcome of survival without brain injury will be determined at 36 weeks' postmenstrual age and the second co-primary outcome (survival without neurodevelopmental disability) will be assessed at 2 years of age, corrected for prematurity. Discussion: It is essential that appropriately designed trials be performed to define the most appropriate management strategies for managing low BP in extremely preterm babies.

BackgroundThe majority of coronary bifurcation lesions are treated with a provisional single‐stent strategy rather than an up‐front 2‐stent strategy. This approach is supported by multiple randomized controlled clinical trials with short‐ to medium‐term follow‐up; however, long‐term follow‐up data is evolving from many data sets.Methods and ResultsMeta‐analysis of randomized controlled trials evaluating long‐term outcomes (≥1 year) according to treatment strategy for coronary bifurcation lesions. Nine randomized controlled trials with 3265 patients reported long‐term clinical outcomes at mean weighted follow‐up of 3.1±1.8 years. Provisional single stenting was associated with lower all‐cause mortality (2.94% versus 4.23%; risk ratio: 0.69; 95% confidence interval, 0.48–1.00; P=0.049; I2=0). There was no difference in major adverse cardiac events (15.8% versus 15.4%; P=0.79), myocardial infarction (4.8% versus 5.5%; P=0.51), target lesion revascularization (9.3% versus 7.6%; P=0.19), or stent thrombosis (1.8% versus 1.6%; P=0.28) between the groups. Prespecified sensitivity analysis of long‐term mortality at a mean of 4.7 years of follow‐up showed that the provisional single‐stent strategy was associated with reduced all‐cause mortality (3.9% versus 6.2%; risk ratio: 0.63; 95% confidence interval, 0.42–0.97; P=0.036; I2=0).ConclusionsCoronary bifurcation percutaneous coronary intervention using a provisional single‐stent strategy is associated with a reduction in all‐cause mortality at long‐term follow‐up.