Publications

Corticosteroid insensitivity is a major therapeutic problem for some inflammatory diseases including chronic obstructive pulmonary disease (COPD), and it is known to be induced by reduced histone deacetylase (HDAC)-2 activities via activation of the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study is to evaluate effects of a novel macrolide/fluoroketolide, solithromycin (SOL, CEM-101), on corticosteroid sensitivity induced by oxidative stress.Corticosteroid sensitivity was determined by IC50/EC50 of dexamethasone (Dex) on TNF-α-induced CXCL8 production in U937 monocytic cell line and peripheral blood mononuclear cells (PBMC) from COPD patients. Activities of HDAC and protein phosphatase 2A (PP2A) were measured by fluorescence-based assay in cells exposed to hydrogen peroxide (H2O2). We also investigated steroid insensitive airway neutrophilia in cigarette smoke exposed mice in vivo.SOL (10 μM) restored Dex sensitivity in PBMC from COPD patients, H2O2-treated U937 cells and phorbol 12-myristate 13-acetate-differentiated U937 cells. In addition, SOL restored HDAC activity with concomitant inhibition of Akt phosphorylation as surrogate marker of PI3K activation. The inhibition of Akt phosphorylation by SOL was due to increased PP2A phosphatase activity, which was reduced in COPD and oxidative stress model. Other known macrolides, such as eryhthromycin, clarithromycin and azithromycin, were significantly less effective in these responses. In cigarette smoke-exposed mice, SOL (100 mg kg(-1), po) showed significant but weak inhibition of neutrophilia, whereas Dex (10 mg kg(-1), p.o.) showed no such effect. However, a combination of SOL and Dex inhibited neutrophilia by over 50%.SOL has potential as novel therapy for corticosteroid-insensitive diseases such as COPD.

Background— The factors associated with the occurrence of restenosis after sirolimus-eluting stent (SES) implantation in complex cases are currently unknown. Methods and Results— A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: (1) treatment of acute myocardial infarction, (2) treatment of in-stent restenosis, (3) 2.25-mm diameter SES, (4) left main coronary stenting, (5) chronic total occlusion, (6) stented segment >36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to 11.01; P <0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P <0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P =0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P <0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P =0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P <0.01). Conclusions— Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.

Objective To evaluate effect of strut protrusion (SP) on wall shear stress (WSS) and neointimal growth (NG) 1 and 5 year after implantation of Absorb scaffold. Method 8 patients were selected from Absorb Cohort B. After 3-dimensional reconstruction of coronaries, WSS was quantified using Newtonian steady flow simulation (Figure). At 1-year neointimal thickness (NT) was measured by optical coherence tomography and correlated to WSS and SP post-procedure. Results Median SP was 112.9 (90.8, 133.1) μm. A logarithmic (log) inverse relationship between SP and post-procedure WSS (r=−0.425 p<0.001 correlation coefficients range: −0.143 to −0.553) was observed whereas a correlation between baseline log transformed WSS and NT (r=−0.451 p<0.001 correlation coefficients range: −0.140 to −0.662) was documented at 1 year. Mixed effects analysis between baseline log transformed WSS and NT at follow up yielded a slope of 30 μm/ln Pascal (Pa) and a y-intercept of 98 μm. As result of NG, flow area decreased from 6.91 (6.53, 7.48) mm2 post-implantation to 5.65 (5.47, 6.02) mm2 at 1 year (p=0.01) and to 5.75±1.37 mm2 at 5 years (p=0.024). Vessel surface with low WSS (<1 Pa) decreased from post-procedure (42%) to 1 year (35.9%) and 5 years (15.2%) (p-overall<0.0001). Conclusion SP disturbs laminar flow, creates region of low WSS that is mechanistically associated with NG and lumen area reduction. This observation would suggest thin strut with effective embedment would reduce NG and improve WSS towards physiological values.

No abstract is provided for this article.

No abstract is provided for this article.

Background: There is accumulating evidence that theophylline has anti‐inflammatory or immunomodulatory effects. This may be, in part, mediated via an upregulation in the production of the anti‐inflammatory cytokine interleukin (IL)‐10. We determined whether low‐dose theophylline (LDT) would increase the production of IL‐10, and attenuate the production of proinflammatory cytokines by alveolar macrophages. Methods: In a double‐blind, placebo‐controlled, crossover study involving 15 steroid‐free patients with mild asthma, fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed at the end of the treatment and placebo periods. Alveolar macrophages were cultured in vitro , and we measured their release of IL‐10, GM‐CSF, and TNF‐α. We also measured IL‐10 production in whole blood together with the number of monocytes and T cells expressing intracellular IL‐10 by flow cytometry. Results: LDT did not increase the production of IL‐10, or attenuate the production of GM‐CSF or TNF‐α by alveolar macrophages. However, after theophylline treatment, there was a significant reduction in mean (SD) (95% CI) BAL eosinophil number from 3.4 (1.7)% (95% CI 2.4–4.4) to 1.7 (1.0)% (95% CI 1.1–2.3) compared with placebo ( P <0.05). Similarly, there was no increase in whole‐blood IL‐10 release or in the number of monocytes and T cells expressing intracellular IL‐10 after treatment. Conclusions: LDT has an anti‐inflammatory effect in asthma; however, this effect is not mediated via the production of IL‐10 or the attenuation of GM‐CSF or TNF‐α. The mechanisms of theophylline activity remain to be determined.

Earlier generation self-expanding stents (SExS) showed high restenosis rates and long-term stent over-expansion. A novel SExS with reduced outward expansive force has been developed to overcome these limitations. This first-in-human study aimed to evaluate the safety and feasibility of the low pressure self-expanding nitinol-based vProtect™ luminal shield (LS) in the treatment of intermediate coronary lesions.A total of 29 patients with clinical evidence of myocardial ischaemia and intermediate de novo coronary lesions were included. The LS was deployed after low-pressure balloon pre-dilatation. Acute procedural and device success was achieved in all patients. Angiographic follow-up at nine months showed an in-stent lumen loss of 0.50±0.30 mm and a binary restenosis rate of 10.3%. There were no cases of late LS over-expansion or acute/late malapposition as evaluated by intravascular ultrasound (IVUS). The cumulative major adverse cardiac events (MACE) rate at nine months was 10.3%, consisting of three target lesion revascularisations, with no cases of death, myocardial infarction or stent thrombosis.Implantation of the LS in non-complex coronary lesions of intermediate severity was feasible, safe, and resulted in low rates of late loss and restenosis. IVUS analysis at nine months showed favourable mechanical properties of the LS without evidence of late device over-expansion.

<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.

No abstract is provided for this article.

The clinical robustness of contrast-videodensitometric (VD) assessment of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) has been demonstrated. Correct acquisition of aortic root angiography for VD assessment, however, is hampered by the opacified descending aorta and by individual anatomic peculiarities. The aim of this study was to use preprocedural multi-slice computed tomography (MSCT) to optimize the angiographic projection in order to improve the feasibility of VD assessment.Methods and Results:In 92 consecutive patients, post-TAVI AR (i.e., left ventricular outflow tract [LVOT] AR) was assessed on aortic root angiograms using VD software. The patients were divided into 2 groups: The first group of 54 patients was investigated prior to the introduction of the standardized acquisition protocol; the second group of 38 consecutive patients after implementation of the standardized acquisition protocol, involving MSCT planning of the optimal angiographic projection. Optimal projection planning has dramatically improved the feasibility of VD assessment from 57.4% prior to the standardized acquisition protocol, to 100% after the protocol was implemented. In 69 analyzable aortograms (69/92; 75%), LVOT-AR ranged from 3% to 28% with a median of 12%. Inter-observer agreement was high (mean difference±SD, 1±2%), and the 2 observers' measurements were highly correlated (r=0.94, P<0.0001).Introduction of computed tomography-guided angiographic image acquisition has significantly improved the analyzability of the angiographic VD assessment of post-TAVI AR.

BACKGROUNDStatins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma.METHODSThirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1, and symptoms using the COPD Assessment Test (CAT).RESULTSAt 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, –16.4 pg/mL, P = .01; –48.6 pg/mL, P < .001; –45.3 pg/mL, P = .002; and –190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P < .001; 1.02, P < .001; and 0.47, P < .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, –0.16 × 106Doe C Bafadhel M Siddiqui S et al.Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD.Chest. 2010; 138: 1140-1147Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, P = .004; –14.1%, P < .001; and –3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments.CONCLUSIONSSimvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.TRIAL REGISTRYClinicalTrials.gov; No.: NCT01944176; www.clinicaltrials.gov Statins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma. Thirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1, and symptoms using the COPD Assessment Test (CAT). At 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, –16.4 pg/mL, P = .01; –48.6 pg/mL, P < .001; –45.3 pg/mL, P = .002; and –190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P < .001; 1.02, P < .001; and 0.47, P < .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, –0.16 × 106Doe C Bafadhel M Siddiqui S et al.Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD.Chest. 2010; 138: 1140-1147Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, P = .004; –14.1%, P < .001; and –3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments. Simvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.