Publications

Inhaled Budesonide in the Treatment of Early COVID-19 Illness: A Randomised Controlled Trial

Background: Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. Methods: We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results: 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Conclusion: Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.Trial Registration: ClinicalTrials.gov number, NCT04416399Funding: Oxford NIHR Biomedical Research Centre and AstraZenecaDeclaration of Interests: Dr. Ramakrishnan reports grants and non-financial support from Oxford Respiratory NIHR BRC, during the conduct of the study; non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside the submitted work; . Dr. Nicolau has nothing to disclose. Mrs Langford has nothing to disclose. Mr. Mahdi has nothing to disclose. Mrs Helen Jeffers reports personal fees from AstraZeneca, outside the submitted work; . Miss Mwasuku has nothing to disclose. Mrs Krassowska has nothing to disclose. Dr Fox has nothing to disclose. Dr Binnian has nothing to disclose. Dr Glover has nothing to disclose. Dr Bright has nothing to disclose. Dr. Butler reports grants from National Institute for Health Research (NIHR), Roche Molecular Diagnostics, Janssen Pharmaceuticals, and various public funding bodies for research related to diagnostics and infections. He has revcied personal fees from Pfizer INC, Roche Diagnostics, and Janssen Pharmaceuticals, outside the submitted work. Dr. Cane has nothing to disclose. Mr. Halner has nothing to disclose. Dr. Matthews has nothing to disclose. Dr. Donnelly reports grants from AstraZeneca, from Boehringer-Ingelheim, outside the submitted work; . Dr. Simpson has nothing to disclose. Dr Baker has nothing to disclose. Dr. Fadai has nothing to disclose. Dr. Peterson reports personal fees from AstraZeneca, outside the submitted work; . Mr. Bengtsson reports personal fees from AstraZeneca, outside the submitted work; Dr. Barnes reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from Covis, during the conduct of the study; Dr. Russell reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi UK, personal fees from Glaxo-SmithKline, during the conduct of the study; . Dr. Bafadhel reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GSK, other from Albus Health, ProAxsis, outside the submitted work; .Ethics Approval Statement: The trial was sponsored by the University of Oxford, and was approved by the Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority.The ethical approval number is 20/HRA/2531.

Leukotriene B4 Activates the NADPH Oxidase in Eosinophils by a Pertussis Toxin-Sensitive Mechanism That Is Largely Independent of Arachidonic Acid Mobilization

Abstract Experiments were designed to investigate whether leukotriene (LTB4) receptors can couple directly to phospholipase A2 (PLA2) in guinea pig eosinophils and the role of endogenous arachidonic acid (AA) in LTB4-induced activation of the NADPH oxidase. LTB4 (EC50 ∼ 16 nM) and AA (EC50 ∼ 6 μM) generated hydrogen peroxide (H2O2) in a concentration-dependent manner and at an equivalent maximum rate (5–6 nmol/min/106 cells). LTB4 stimulated PLA2 over a similar concentration range that activated the NADPH oxidase, although kinetic studies revealed that the release of [3H]AA (t1/2 ∼ 2 s) preceded H2O2 generation (t1/2 > 30 s). Pretreatment of eosinophils with pertussis toxin abolished the increase in inositol(1,4,5)trisphosphate mass, [Ca2+]c, [3H]AA release, and H2O2 generation evoked by LTB4. Qualitatively identical results were obtained in eosinophils in which phospholipase C (PLC) was desensitized by 4β-phorbol 12,13-dibutyrate with the exception that [3H]AA release was largely unaffected. Additional studies performed with the protein kinase C inhibitor, Ro 31-8220, and under conditions in which Ca2+ mobilization was abolished, provided further evidence that LTB4 released [3H]AA independently of signal molecules derived from the hydrolysis of phosphatidylinositol(4,5)bisphosphate by PLC. Pretreatment of eosinophils with the PLA2 inhibitor, mepacrine, abolished LTB4-induced [3H]AA release at a concentration that inhibited H2O2 by only 36%. Collectively, the results of this study indicate that agonism of LTB4 receptors on guinea pig eosinophils mobilizes AA by a mechanism that does not involve the activation of PLC. In addition, although LTB4 effectively stimulated PLA2, a central role for AA in the activation of the NADPH oxidase was excluded.

Novel cementitious materials produced from incinerator bottom ash

Clinical and angiographic follow-up after overlapping implantation of polytetrafluoroethylene covered stents with drug eluting stents.

Polytetrafluoroethylene-covered stents (PCS) were recently proposed as a new modality mainly for the treatment of saphenous vein graft lesions, but restenosis occurring principally at the edges restricted their clinical use in the management of coronary aneurysms and perforations.To investigate the safety and effectiveness of the overlapping implantation of drug-eluting stents (DES) with PCS in clinical scenarios where the latter are indicated.Since April 2002, when DES were introduced in clinical practice, 14 consecutive patients were -treated with overlapping implantation of PCS with DES in 3 centres. Seven patients were treated for coronary aneurysms, 5 for coronary perforations and 2 for branch occlusion. The incidence of any major adverse cardiac events defined as death, myocardial infarction (MI), and target vessel revascularisation (TVR) was retrospectively evaluated. A control angiography was available in 13 patients, and quantitative coronary angiography was performed before and after the intervention and at follow-up to evaluate restenosis rate and late loss.At a mean clinical follow-up of 21.9 months there were no deaths or MI's, while one patient with occlusive restenosis underwent successful TVR (7.7%). At angiographic follow-up (mean: 9.7 months) there was one patient with restenosis (7.7%), who had a total occlusion. After excluding the patient with the occlusive restenosis mean diameter stenosis was 22.4+/-11.7% and late loss was 0.18+/-0.35 mm at follow-up. No early or late stent thrombosis occurred.Overlapping implantation of PCS with DES seems to be a safe and effective therapeutic modality demonstrating a low incidence of clinical and angiographic restenosis.

Do systemic risk factors impact invasive findings from virtual histology? Insights from the international virtual histology registry

Cardiovascular risk factors such as elevated serum lipid levels are important in the development of coronary atherosclerosis. Radiofrequency (RF) analysis of intravascular ultrasound [IVUS, Virtual histology™ (VH)] offers a unique tool to study the composition of coronary atherosclerotic plaque in vivo. We used data from the multicentre VH registry to assess the association between cardiovascular risk factors and coronary plaque volume and composition. Between August 2004 and July 2006, 990 patients in 42 centres were enrolled in a prospective, multicentre, non-randomized global VH registry. Coronary artery imaging was performed by conventional IVUS and RF-IVUS. The four RF-IVUS plaque components [dense calcium (DC), necrotic core (NC), fibrous (F) tissue, and fibro fatty (FF)] were analysed in every recorded frame. The results were expressed as mean cross-sectional areas, absolute volume, and percentage of total plaque volume. Risk factor assessment included evaluation of family history of previous myocardial infarction (MI), past or current smoking, diabetes mellitus, hypertension, and the laboratory measurements. Patients with diabetes had an increased relative proportion of NC (6.47 ± 0.28 vs. 5.86 ± 0.14%, P = 0.037) and DC (4.58 ± 0.27 vs. 3.90 ± 0.14%, P = 0.017), and patients with hypertension had an increased relative proportion of FF, DC (4.35 ± 0.16 vs. 3.57 ± 0.17%, P = 0.02) and NC (6.24 ± 0.17 vs. 5.60 ± 0.19%, P = 0.01). Compared with patients with LDL-C <100 mg/dL, patients with LDL-C >160 mg/dL had higher plaque volume (342.1 ± 26.2 vs. 318.6 ± 10.7 mm3). Linear regression analysis showed a correlation between the level of HDL-C and F (r = −0.149, P < 0.01), FF (r = −0.106, P < 0.01), and NC (r = −0.90, P < 0.05). The level of LDL correlated with F (r = 0.110, P < 0.01). Patients with prior MI have an increased percentage of F (30.03 ± 0.59 vs. 28.20 ± 0.37%, P = 0.009). Smoking had no relevant effect on plaque composition. Treatment with acetylsalicylacid and statins reduced FF with altering plaque volume. Radiofrequency-IVUS detects marked differences in coronary plaque composition related to the risk factor profile with particular focus on lipid levels. Greater amounts of NC were associated with diabetes, hypertension, MI, and low HDL-C. The effects of treatment of changes related to plaque composition are underway.

Future research in chronic obstructive pulmonary disease

Treatment options for multivessel coronary artery disease

‘Continuous improvement of devices and techniques has progressed from the limited treatment of single, simple lesions to the extensive management of multiple and severely complex stenoses.’ Sophia Vaina, Keiichi Tsuchida and Patrick W Serruys Author for correspondence Erasmus Medical Center, Thoraxcenter, Ba 583, Dr Molewaterplein 40, 3015 GD Rotterdam,The Netherlands Tel.: +31 104 635 260 Fax: +31 104 369 154 p.w.j.c.serruys@erasmusmc.nl Expert Rev. Cardiovasc. Ther. 4(2), 143–147 (2006)

Prediction of Left Ventricular Function After Drug-Eluting Stent Implantation for Chronic Total Coronary Occlusions

Objectives We studied the effect of drug-eluting stent implantation for chronic total coronary occlusion (CTO) on left ventricular volumes and function and assessed the predictive value of magnetic resonance imaging (MRI) performed before revascularization. Background The effect of recanalization of CTO on long-term left ventricular function and the value of myocardial viability assessment with MRI is incompletely understood. Methods Twenty-seven patients underwent contrast-enhanced MRI before and five months after successful drug-eluting stent implantation for CTO. A CTO was defined as a complete occlusion of a major epicardial coronary artery existing for at least six weeks (mean, 7 ± 5 months). Myocardial wall thickening and left ventricular volumes were quantified on cine-images, and the transmural extent of infarction (TEI) was scored on delayed-enhancement images. Results A significant decrease in mean end-systolic volume index (34 ± 13 ml/m2to 31 ± 13 ml/m2; p = 0.02) and mean end-diastolic volume index (84 ± 15 ml/m2to 79 ± 15 ml/m2; p < 0.002) was observed, whereas the mean ejection fraction did not change significantly (61 ± 9% to 62 ± 11%; p = 0.54). The extent of the left ventricle that was dysfunctional but viable before revascularization was related to improvement in end-systolic volume index (R = 0.46; p = 0.01) and ejection fraction (R = 0.49; p = 0.01) but not to the end-diastolic volume index (R = 0.10; p = 0.53). Segmental wall thickening improved significantly in segments with <25% TEI (21 ± 15% to 35 ± 25%; p < 0.001), tended to improve in segments with 25% to 75% TEI (18 ± 22% to 27 ± 22%; p = 0.10), whereas segments with >75% TEI did not improve (4 ± 14% to −9 ± 14%; p = 0.54). Conclusions Drug-eluting stent implantation for a CTO has a beneficial effect on left ventricular volumes and function that can be predicted by performing MRI before revascularization.

Long-term effectiveness and safety of the sirolimus-eluting BiOSS LIM® dedicated bifurcation stent in the treatment of distal left main stenosis: an international registry

Aims:The aim of this study was to assess prospectively the effectiveness and safety of a new version of the dedicated bifurcation BiOSS stent, the sirolimus-eluting BiOSS LIM, for the treatment of distal left main (LM) stenosis. Methods and results:This was a prospective international registry which enrolled patients with NSTE-ACS or stable angina.Provisional T-stenting was the mandated strategy.The primary endpoint was the cumulative rate of cardiac death, myocardial infarction (MI) and target lesion revascularisation (TLR) at 12 months.Twelve-month quantitative coronary angiography endpoints included late lumen loss and percent diameter stenosis.A total of 74 patients with distal LM stenosis were enrolled.Seventy-three of the 74 patients (aged 67±9 years, 23% women, 20.3% NSTE-ACS, SYNTAX score 22.4±4.4)were successfully treated with the BiOSS LIM stent, with additional side branch placement of regular DES in 11 patients (14.9%).Periprocedural MI occurred in one (1.4%)patient.The 12-month MACE rate was 9.5% without cardiac death or definite stent thrombosis.TLR and MI rates were 6.8% (n=5) and 2.7% (n=2), respectively. Conclusions:The use of the BiOSS LIM dedicated bifurcation stent for the treatment of distal LM stenosis was feasible and safe, with promising long-term clinical effectiveness.

Guidewire navigation in coronary artery stenoses using a novel magnetic navigation system: First clinical experience

The objective of this study was to investigate the efficacy of guidewire navigation across coronary artery stenoses using magnetic navigation system (MNS) versus conventional navigation. The MNS is a novel option to facilitate access to target lesions, particularly in tortuous vessels. In an experimental study using a challenging vessel phantom, magnetic‐navigated guidewire passage has been reported to reduce fluoroscopy and procedure time significantly. Both magnetic and manual guidewire navigation were attempted in 21 consecutive diseased coronary arteries. The study endpoint was defined as an intraluminal wire position distal to the stenosis. Procedural success was defined as successful guidewire passage without procedural events. Procedure time, amount of contrast, fluoroscopy time, and radiation dose/area product (DAP) were evaluated. There were no procedural events related to either guidewire. Although the lesions attempted had relatively simple and straightforward characteristics, significantly shorter procedure and fluoroscopy time were observed for manual guidewire navigation compared to MNS (median, 40 vs. 120 sec, P = 0.001; 38 vs. 105 sec, P = 0.001, respectively). Contrast amount and DAP were higher in MNS than in conventional method (median, 13 vs. 9 ml, P = 0.018; 215 vs. 73 Gym 2 , P = 0.002, respectively). The magnetic wire did not cross in two vessels. Guidewire navigation using MNS presented a novel, safe, and feasible approach to address coronary artery lesions. Clinical studies are needed to evaluate the potential benefit of the MNS in more complex coronary lesions and tortuous anatomy. © 2006 Wiley‐Liss, Inc.

Elevated concentrations of CXCL8 in the nasal mucosal lining fluid of COPD patients as an accessible surrogate measure of bronchial levels

<b>Introduction:</b> CXCL8 is a neutrophil chemoattractant involved in the pathogenesis of COPD with increased levels reported in both induced sputum and BAL fluid. The upper respiratory tract is histologically and immunologically related to the bronchi and exposed to the same noxious stimuli in COPD. It may represent a more easily accessible surrogate measure of CXCL8 and other inflammatory biomarkers. <b>Hypothesis:</b> Concentrations of CXCL8 are increased in the nasal mucosal lining fluid (MLF) of COPD patients compared with controls and are a surrogate measure for bronchial CXCL8. <b>Methods:</b> A synthetic absorptive matrix (SAM; nasosorption) was used to sample the nasal MLF of 13 stable COPD patients, 12 healthy non-smokers (NS) and 10 smokers (Sm). Less severe COPD patients (FEV₁≥50%; n=8) underwent bronchoscopy to obtain paired samples of bronchial MLF using SAM (bronchosorption). Concentrations of CXCL8 were measured in the eluates by ELISA. <b>Results:</b> Nasal CXCL8 was higher in COPD when compared to NS but not Sm (Table). Mean (± SEM) concentrations of bronchial CXCL8 were 0.9±0.2 ng/ml in COPD and levels correlated with paired nasal samples (r=-0.88, p&lt;0.01). Concentrations of nasal CXCL8 also correlated with FEV₁ % predicted in COPD (r=-0.83, p&lt;0.001) but not age, pack years, FEV₁ or FVC. <b>Conclusion:</b> Nasal CXCL8 is elevated in COPD and may reflect bronchial levels. Measuring CXCL8 by nasosorption may provide a non-invasive biomarker to further explore inflammation during stable disease, exacerbations or modulation by novel treatments.

PHOSPHODIESTERASE INHIBITORS: WILL THEY REPLACE THEOPHYLLINE?

Education through autobiography

Sputum Plasminogen Activator Inhibitor-1 Elevation by Oxidative Stress-Dependent Nuclear Factor-κB Activation in COPD

Brief Depression Screening with the PHQ-2 Associated with Prognosis Following Percutaneous Coronary Intervention with Paclitaxel-Eluting Stenting

Depression is associated with adverse prognosis in cardiac patients, warranting the availability of brief and valid instruments to identify depressed patients in clinical practice. We examined whether the two-item Patient Health Questionnaire (PHQ-2) was associated with adverse events in percutaneous coronary intervention (PCI) patients treated with paclitaxel-eluting stenting (using the continuous score and various cutoffs), overall and by gender. Prospective follow-up study. Consecutive PCI patients (n = 796) seen at a university medical centre. PHQ-2 at baseline. The study endpoint was an adverse event, defined as a combination of death or non-fatal myocardial infarction (MI) at follow-up (mean of 1.4 years). At follow-up, 47 patients had experienced an adverse event. Using the continuous score of the PHQ-2 and the recommended cutoff ≥3, depressive symptoms were not associated with adverse events (ps > 0.05). Using a cutoff ≥2, depressive symptoms were significantly associated with adverse events (HR: 1.89; 95% CI: 1.06–3.35) and remained significant in adjusted analysis (HR: 1.90; 95% CI: 1.05–3.44). Depressive symptoms were associated with an increased risk of adverse events in men (HR: 2.69; 95% CI: 1.36–5.32) but not in women (HR: 0.76; 95% CI: 0.24–2.43); these results remained in adjusted analysis. Depression screening with a two-item scale and a cutoff score of ≥2 was independently associated with adverse events at follow-up. The PHQ-2 is a brief and valid measure that can easily be used post PCI to identify patients at risk for adverse health outcomes.

In vitro study of FFR, QCA, and IVUS for the assessment of optimal stent deployment

We tested whether fractional flow reserve (FFR) discriminates between suboptimally and optimally deployed stents. Latex tubes (diameter ⊘ = 4 mm) with diameter stenosis 40% (n = 3), 50% (n = 3) and 60% (n = 3) were tested in a pulsatile flow system, using water. Measurements were done at baseline (n = 9; FFR/QCA) and after suboptimal (SOD; 3‐mm balloon at 8 atm) and optimal (OD; 4 mm balloon at 16 atm) deployment of a 35‐mm stent (n = 6; FFR/QCA/IVUS). Varying Q from 150 to 50 ml/min increased FFR by 2–7%. Conversely, at 100 ml/min, FFR increased by only 0.8% from SOD to OD ( P &lt; 0.05). Extrapolating data to blood flow, the gain in FFR from SOD to OD is less than 5% for Q = 100 ml/min, while FFR may increase by 15–20% by changes in blood flow from 50 to 150 ml/min. We conclude that IVUS and QCA are more appropriate for the assessment of optimal stent deployment. Cathet Cardiovasc Intervent 2001;54:363–375. © 2001 Wiley‐Liss, Inc.

The Effect of Variable Dose and Release Kinetics on Neointimal Hyperplasia Using a Novel Paclitaxel-Eluting Stent Platform

Objectives The aim of this study was to evaluate the effect of variable dose and release kinetics of paclitaxel on neointimal hyperplasia. Background Conventional paclitaxel-eluting stents use a durable polymer coating as a vehicle for drug delivery. The Conor stent (Conor Medsystems, Menlo Park, California) with intra-strut wells and erodable polymer is specifically designed for drug delivery with programmable pharmacokinetics. Methods Two hundred and forty-four patients with single vessel disease received either a bare metal Conor stent (n = 53) or one of six different release formulations that varied in dose (10 or 30 μg) and elution release kinetics (first order, zero order), direction (abluminal, luminal), and duration (5, 10, and 30 days). End points at six months (bare stent group) and at four months (eluting stent groups) were angiographic late loss and neointimal tissue volume by intravascular ultrasound and the rate of major adverse cardiac events (MACE). Results The lowest in-stent late loss (0.38 mm, p <0.01, and 0.30 mm, p <0.01) and volume obstruction (8%, p <0.01, and 5%, p <0.01) were observed with the 10-μg and 30-μg doses in the 30-day release groups respectively, whereas the highest in-stent late loss (0.88 mm), volume obstruction (26%), and restenosis rate (11.6%) were observed in the bare stent group. The overall MACE rate of the eluting stent group was 8.6%: death 0.5%, myocardial infarction 2.7%, and target lesion revascularization (TLR) 5.3%. Sub-acute thrombosis was 0.5%. The TLR rates in the two 30-day release groups were 0% and 3.4%. Conclusions This novel eluting stent platform, using an erodable polymer with complete elution of low doses of paclitaxel, is safe. The inhibition of the in-stent neointimal hyperplasia was best in the long release groups.

Mitwirkende Autoren