Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

Background: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance.<p></p> Trial Design: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed.<p></p> Conclusions: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation

Rationale and design of the PRognostic Importance of MIcrovascular Dysfunction in asymptomatic patients with Aortic Stenosis (PRIMID-AS): a multicentre observational study with blinded investigations

Introduction: Aortic stenosis (AS) is the commonest valve disorder in the developed world requiring surgery. Surgery in patients with severe asymptomatic AS remains controversial. Exercise testing can identify asymptomatic patients at increased risk of death and symptom development, but with limited specificity, especially in older adults. Cardiac MRI (CMR), including myocardial perfusion reserve (MPR) may be a novel imaging biomarker in AS. Aims (1) To improve risk stratification in asymptomatic patients with AS and (2) to determine whether MPR is a better predictor of outcome than exercise testing and brain natriuretic peptide (BNP). Method/design Multicentre, prospective observational study in the UK, comparing MPR with exercise testing and BNP (with blinded CMR analysis) for predicting outcome. Population 170 asymptomatic patients with moderate-to-severe AS, who would be considered for aortic valve replacement (AVR). Primary outcome Composite of: typical symptoms necessitating referral for AVR and major adverse cardiovascular events. Follow-up: 12–30 months (minimum 12 months). Primary hypothesis MPR will be a better predictor of outcome than exercise testing and BNP. Ethics/dissemination The study has full ethical approval and is actively recruiting patients. Data collection will be completed in November 2014 and the study results will be submitted for publication within 6 months of completion. ClinicalTrials.gov identifier NCT01658345

Myocardial Perfusion Reserve but not fibrosis predicts outcomes in initially asymptomatic patients with moderate to severe aortic stenosis : the PRognostic Importance of MIcrovascular Dysfunction in AS study- PRIMID AS

Peer reviewedPublisher PD

LTB4 Is a Signal-Relay Molecule during Neutrophil Chemotaxis

SummaryNeutrophil recruitment to inflammation sites purportedly depends on sequential waves of chemoattractants. Current models propose that leukotriene B4 (LTB4), a secondary chemoattractant secreted by neutrophils in response to primary chemoattractants such as formyl peptides, is important in initiating the inflammation process. In this study we demonstrate that LTB4 plays a central role in neutrophil activation and migration to formyl peptides. We show that LTB4 production dramatically amplifies formyl peptide-mediated neutrophil polarization and chemotaxis by regulating specific signaling pathways acting upstream of actin polymerization and MyoII phosphorylation. Importantly, by analyzing the migration of neutrophils isolated from wild-type mice and mice lacking the formyl peptide receptor 1, we demonstrate that LTB4 acts as a signal to relay information from cell to cell over long distances. Together, our findings imply that LTB4 is a signal-relay molecule that exquisitely regulates neutrophil chemotaxis to formyl peptides, which are produced at the core of inflammation sites

Does neoadjuvant doxorubicin drug-eluting bead transarterial chemoembolization improve survival in patients undergoing liver transplant for hepatocellular carcinoma?

PURPOSE:We aimed to compare the overall (OS) and disease-free survival (DFS) of patients undergoing orthotopic liver transplant (OLT) for hepatocellular carcinoma who did and did not have neoadjuvant doxorubicin drug-eluting bead transarterial chemoembolization (DEB-TACE).METHODS:This is a retrospective study of 94 patients with HCC transplanted between 2000 and 2014 in a single tertiary center. Pre- and postoperative features, DFS and OS were compared between patients who received pre-OLT DEB-TACE (n=34, DEB-TACE group) and those who did not (n=60, non-TACE group). Radiologic and histologic response to neoadjuvant treatment as well as its complications were also studied.RESULTS:There were no significant differences in post-transplantation DFS and OS rates between groups (5-year DFS: 70% in DEB-TACE group vs. 63% in non-TACE group, P = 0.454; 5-year OS: 70% in DEB-TACE group vs. 65% in non-TACE group, P = 0.532). The DEB-TACE group had longer OLT waiting time compared with the non-TACE group (110 vs. 72 days; P = 0.01). On univariate and multivariate analyses, alpha-fetoprotein (AFP) levels >500 ng/mL prior to OLT were associated with decreased OS and DFS regardless of neoadjuvant approach (hazard ratio of 6, P = 0.001 and 5.5, P = 0.002, respectively).CONCLUSION:Patients who underwent neoadjuvant DEB-TACE and OLT for hepatocellular carcinoma had no statistically different OS or DFS at 3 and 5 years from patients undergoing OLT alone

Demographic, multi-morbidity and genetic impact on myocardial involvement and its recovery from COVID-19 : protocol design of COVID-HEART-a UK, multicentre, observational study

Acknowledgements CB acknowledges British Heart Foundation support (RE/18/6134217). GPM is funded by a NIHR Research Professorship (RP‐2017‐08‐ST2‐007). CM is funded by a NIHR Clinician Scientist Award (CS‐2015‐15‐003). VMF and SN acknowledge the NIHR Oxford BRC for support of this study. CBD is in part supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Additional support was provided by the NIHR Leicester Biomedical Research Centre and the NIHR Leeds Clinical Research Facility. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. We thank the patients and staff who have supported this project. Dr. Warren J. Manning served as a Guest Editor for this manuscript. Study Management and Recruitment centres: Grant applicants: JP Greenwood (chief investiga‐ tor), GP McCann, C Berry, M Dweck, J Moon, CM Miller, A Chiribiri, S Prasad, VM Ferreira, C Bucciarelli‐Ducci, D Dawson. Data repository and statistical analysis: Glasgow Clinical Trials Unit. Senior study statistician: Prof A McConnachie, GCTU. Local Principle Investigators and Recruitment Centres: Prof John Green‐ wood, Leeds Teaching Hospitals NHS Trust, UK; Prof Gerry McCann, Glenfield Hospital, Leicester, UK; Prof Dana Dawson, Aberdeen Royal Infirmary, UK; Prof Marc Dweck, Royal Infirmary of Edinburgh, UK; Prof Vanessa Ferreira, JohnRadcliffe Hospital, Oxford, UK; Prof Colin Berry, Queen Elizabeth University Hospital, Glasgow, UK; Dr Peter Swoboda, Pinderfields Hospital, Wakefield, UK; Dr Richard Steeds, Queen Elizabeth Hospital, Birmingham, UK; Prof James Moon, UCL Hospital London, UK; Dr Christopher Miller, Wythenshawe Hospital, Manchester, UK; Dr Timothy Fairbairn, Liverpool Heart and Chest Hospital, UK; Dr Andrew Flett, Southampton General Hospital, UK; Prof Marianna Fontana, Royal Free Hospital, London, UK; Dr Thomas Green, Northumbria NHS Trust, UK; Prof Amedeo Chiribiri, St Thomas’ Hospital, London, UK; Dr Chiara Bucciarelli‐Ducci, University Hospitals Bristol and Weston NHS Trust, UK; Dr Graham Cole, Hammersmith Hospital, London, UK; Prof Sanjay Prasad, Royal Brompton Hospital, London, UK; Dr Adam McDiarmid, Freeman Hospital, New‐ castle Upon Tyne, UK; Dr Nicholas Bunce, St Georges Hospital, London, UK; Dr Prathap Kanagala, Aintree University Hospital, Liverpool, UK; Prof Nicholas Bellenger, The Royal Devon and Exeter Hospital, UK; Dr Tishi Ninan, Swansea Bay University Hospital, UK; Dr Khaled Alfakih, Lewisham University Hospital, London, UK; Prof James Moon, St Bartholomew’s Hospital, London, UK. Funding COVID‐HEART is funded by the National Institute for Health Research (NIHR) and UK Research and Innovation (UKRI) COVID‐19 Rapid Response Rolling Call (Grant Number COV0254), and sponsored by the University of Leeds, UK. The study has been endorsed by the British Society of Cardiovascular Magnetic Resonance (BSCMR) Research Group, and nationally prioritised, and received both BHF‐NIHR Cardiovascular Partnership Flagship Status, and the NIHR Urgent Public Health Group identified it as an Urgent Public Health (UPH) study. Funding for the translation of the patient information leaflets into non‐ English languages was provided by the West Yorkshire and Humber Clinical Research Network (CV070).Peer reviewedPublisher PD

Vascular effects of serelaxin in patients with stable coronary artery disease:A randomized placebo-controlled trial

Aims: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). Methods and results: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. Conclusion: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion

Low-dose alteplase during primary percutaneous coronary intervention according to ischemic time

Background: Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis. Objectives: This study aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time. Methods: This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset (<2 h, n = 107; ≥2 h but <4 h, n = 235; ≥4 h to 6 h, n = 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145). The primary outcome was the amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (available for 396 of 440). Results: Overall, there was no association between alteplase dose and the extent of MVO (p for trend = 0.128). However, in patients with an ischemic time ≥4 to 6 h, alteplase increased the mean extent of MVO compared with placebo: 1.14% (placebo) versus 3.11% (10 mg) versus 5.20% (20 mg); p = 0.009 for the trend. The interaction between ischemic time and alteplase dose was statistically significant (p = 0.018). Conclusion: In patients presenting with ST-segment elevation myocardial infarction and an ischemic time ≥4 to 6 h, adjunctive treatment with low-dose intracoronary alteplase during primary percutaneous coronary intervention was associated with increased MVO. Intracoronary alteplase may be harmful for this subgroup. (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI [T-TIME]; NCT02257294

VERITAS Observations of the gamma-Ray Binary LS I +61 303

LS I +61 303 is one of only a few high-mass X-ray binaries currently detected at high significance in very high energy gamma-rays. The system was observed over several orbital cycles (between September 2006 and February 2007) with the VERITAS array of imaging air-Cherenkov telescopes. A signal of gamma-rays with energies above 300 GeV is found with a statistical significance of 8.4 standard deviations. The detected flux is measured to be strongly variable; the maximum flux is found during most orbital cycles at apastron. The energy spectrum for the period of maximum emission can be characterized by a power law with a photon index of Gamma=2.40+-0.16_stat+-0.2_sys and a flux above 300 GeV corresponding to 15-20% of the flux from the Crab Nebula.Comment: accepted for publication in The Astrophysical Journa