Publications

No abstract is provided for this article.

1. The effects of a new long‐acting inhaled beta 2‐adrenoceptor agonist aerosol formoterol (12 micrograms), on FEV1, and on methacholine‐ induced bronchoconstriction, were compared with those of terbutaline (250 micrograms) and placebo in 12 midly asthmatic subjects. 2. PC20, the concentration of methacholine needed to cause a 20% fall in baseline FEV1, was determined 2 and 5 h after formoterol, terbutaline and placebo on separate days. Baseline PC20 was determined on a different day. 3. Compared with terbutaline and placebo, formoterol hastened recovery from methacholine‐induced bronchoconstriction, and significantly increased mean PC20 (by 2.2‐ and 2.9‐fold at 2 and 5 h respectively). 4. Thus, formoterol has a protective effect against methacholine‐induced bronchoconstriction which lasts for at least 5 h.

Objectives The aim of this study was to assess acute regurgitation following transcatheter aortic valve replacement, comparing different implanted transcatheter heart valves. Background Regurgitation following transcatheter aortic valve replacement influences all-cause mortality. Thus far, no quantitative comparison of regurgitation among multiple commercially available transcatheter heart valves has been performed. Methods Aortograms from a multicenter cohort of consecutive 3,976 transcatheter aortic valve replacements were evaluated in this pooled analysis. A total of 2,258 (58.3%) were considered analyzable by an independent academic core laboratory using video densitometry. Results of quantitative regurgitation are shown as percentages. The valves evaluated were the ACURATE (n = 115), Centera (n = 11), CoreValve (n = 532), Direct Flow Medical (n = 21), Evolut PRO (n = 95), Evolut R (n = 295), Inovare (n = 4), Lotus (n = 546), Lotus Edge (n = 3), SAPIEN XT (n = 239), and SAPIEN 3 (n = 397). For the main analysis, only valves with more than 50 procedures (7 types) were used. Results The Lotus valve had the lowest mean regurgitation (3.5 ± 4.4%), followed by Evolut PRO (7.4 ± 6.5%), SAPIEN 3 (7.6 ± 7.1%), Evolut R (7.9 ± 7.4%), SAPIEN XT (8.8 ± 7.5%), ACURATE (9.6 ± 9.2%) and CoreValve (13.7 ± 10.7%) (analysis of variance p < 0.001). The only valves that statistically differed from all their counterparts were Lotus (as the lowest regurgitation) and CoreValve (the highest). The proportion of patients presenting with moderate or severe regurgitation followed the same ranking order: Lotus (2.2%), Evolut PRO (5.3%), SAPIEN 3 (8.3%), Evolut R (8.8%), SAPIEN XT (10.9%), ACURATE (11.3%), and CoreValve (30.1%) (chi-square p < 0.001). Conclusions In this pooled analysis stemming from daily clinical practice, the Lotus valve was shown to have the best immediate sealing. This analysis reflects the objective evaluation of regurgitation by an academic core laboratory (nonsponsored) in a real-world cohort of patients using a quantitative technique.

Aims In addition to patients with pure/predominant aortic stenosis (PAS), real-world transcatheter aortic valve implantation (TAVI) referrals include patients with mixed aortic valve disease (MAVD; severe stenosis+moderate-severe regurgitation). We sought to compare TAVI outcomes in patients with MAVD vs. PAS. Methods and results Out of 793 consecutive patients undergoing TAVI, 106 (13.4%) had MAVD. Patients with MAVD were younger and had a higher operative risk, a more severe adverse cardiac remodelling, and a worse functional status than patients with PAS. Moderate-severe prosthetic valve regurgitation (PVR) was significantly more frequent in patients with MAVD than in patients with PAS (15.7% vs. 3.6%, p=0.003), even after propensity-score and multivariable adjustments. Moderate-severe PVR was associated with increased one-year mortality in patients with PAS (log-rank p=0.002), but not in patients with MAVD (log-rank p=0.27). Eventually, all-cause and cardiac mortality as well as the functional capacity were similar in the two study groups up to one year. Conclusions A significant proportion of patients referred for TAVI in a real-world registry has MAVD. Moderate-severe AR at baseline can influence the rate and modify the clinical sequelae of post-TAVI PVR. Eventually, clinical outcomes in patients with MAVD are comparable to those in patients with PAS in the acute and midterm phases, in spite of a baseline higher risk. MAVD should not be considered a contraindication for TAVI.

Cigarette smoking is associated with an increased risk of respiratory tract infections, chronic airway disease, and cardiovascular diseases, all of which may be modulated by endogenous nitric oxide (NO). We have investigated whether cigarette smoking reduces the production of endogenous NO. We compared exhalations of 41 current cigarette smokers with normal lung function and 73 age-matched non-smoking controls. Peak exhaled NO levels were measured by a modified chemiluminescence analyzer. The effects of inhaling a single cigarette in smokers were also measured. In control subjects we also measured the effects of inhalation of NO itself and carbon monoxide, both constituents of tobacco smoke. Peak exhaled NO concentrations were significantly reduced in smokers (42 +/- 3.9 compared with 88 +/- 2.7 parts per billion in nonsmokers, p < 0.01), with a significant relation between the exhaled NO and cigarette consumption (r = 0.77, p < 0.001). Smoking a single cigarette also significantly (p < 0.02), but transiently, reduced exhaled NO. Inhalation of carbon monoxide and NO had no effect on exhaled NO in normal subjects. Cigarette smoking decreased exhaled NO, suggesting that it may inhibit the enzyme NO synthase. Since endogenous NO is important in defending the respiratory tract against infection, in counteracting bronchoconstriction and vasoconstriction, and in inhibiting platelet aggregation, this effect may contribute to the increased risks of chronic respiratory and cardiovascular disease in cigarette smokers.

Inhaled corticosteroids decrease airway responsiveness in asthma partly through suppression of airway inflammation. We have previously demonstrated that inhaled budesonide reduced airway responsiveness to the mast cell stimulus adenosine-5 ′ -monophosphate (AMP) to a threefold greater extent than to methacholine and sodium metabisulfite, suggesting that AMP responsiveness may be a more sensitive marker of airway inflammation and steroid action in order to assess a dose–response relationship. To investigate this, we studied the effects of three doses of the novel corticosteroid ciclesonide (50 μ g, 200 μ g, and 800 μ g) inhaled as a dry powder twice daily on airway responsiveness to AMP and inflammatory parameters in induced sputum. In a three-parallel-dose group, double-blind, placebo-controlled, randomized, crossover study, with a washout period of 3 to 8 wk, a total of 29 patients with mild to moderate allergic asthma underwent AMP challenge and sputum induction before and after 14 d of treatment with ciclesonide or matched placebo. Compared with placebo, ciclesonide 100 μ g, 400 μ g, and 1,600 μ g daily reduced airway responsiveness to AMP by 1.6 (95% confidence interval [CI], − 0.1 to 3.4, not significant [NS]), 2.0 (95% CI, 0.4 to 3.6, p < 0.05), and 3.4 (95% CI, 2.3 to 4.4, p < 0.05) doubling doses, respectively, and this reduction in airway responsiveness was dose-dependent (p = 0.039). A significant reduction in the percentage of eosinophils in induced sputum was observed after 400 μ g and 1,600 μ g daily ciclesonide (p < 0.05), but this was not dose-dependent. Sputum eosinophil cationic protein (ECP) was significantly reduced after 400 μ g daily ciclesonide only (p < 0.05). Thus, in patients with mild to moderate asthma, assessment of airway responsiveness to AMP, rather than inflammatory parameters in induced sputum, represents a sensitive method to evaluate a dose–response relationship of an inhaled corticosteroid and may have applications in evaluating other novel inhaled corticosteroids.

Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.

Transcatheter aortic valve implantation (TAVI) is invariably associated with the risk of clinically manifest transient or irreversible neurologic impairment. We sought to investigate the incidence and causes of clinically manifest stroke during TAVI. A total of 214 consecutive patients underwent TAVI with the Medtronic-CoreValve System from November 2005 to September 2011 at our institution. Stroke was defined according to the Valve Academic Research Consortium recommendations. Its cause was established by analyzing the point of onset of symptoms, correlating the symptoms with the computed tomography-detected defects in the brain, and analyzing the presence of potential coexisting causes of stroke, in addition to a multivariate analysis to determine the independent predictors. Stroke occurred in 19 patients (9%) and was major in 10 (5%), minor in 3 (1%), and transient (transient ischemic attack) in 6 (3%). The onset of symptoms was early (≤24 hours) in 8 patients (42%) and delayed (>24 hours) in 11 (58%). Brain computed tomography showed a cortical infarct in 8 patients (42%), a lacunar infarct in 5 (26%), hemorrhage in 1 (5%), and no abnormalities in 5 (26%). Independent determinants of stroke were new-onset atrial fibrillation after TAVI (odds ratio 4.4, 95% confidence interval 1.2 to 15.6), and baseline aortic regurgitation grade III or greater (odds ratio 3.2, 95% confidence interval 1.1 to 9.3). In conclusion, the incidence of stroke was 9%, of which >1/2 occurred >24 hours after the procedure. New-onset atrial fibrillation was associated with a 4.4-fold increased risk of stroke. In conclusion, these findings indicate that improvements in postoperative care after TAVI are equally, if not more, important for the reduction of periprocedural stroke than preventive measures during the procedure.

No abstract is provided for this article.

<b>Background:</b> COPD is now recognised as a disease of accelerated lung aging, associated with increased cellular senescence, mTOR (mammalian target of rapamycin) signalling and decreased expression of anti-aging molecules, such as sirtuin-1/6. AMPK (5' AMP-activated protein kinase) activation inhibits mTOR, and has been associated with longevity, however its role in regulating senescence in COPD is unclear. <b>Aim:</b> Identify the role of AMPK activation via a pharmacological activator, metformin, on oxidative stress-induced cellular senescence in epithelial cells. <b>Methods:</b> BEAS2B bronchial epithelial cells were exposed to H₂O₂ (100µM) for 48h +/- metformin. Expression of senescence markers and senescence-associated secretory phenotype (SASP) markers were determined by qPCR and Western blotting. <b>Results:</b> Oxidative stress (H₂O₂) increased the expression of senescence markers p21 (9-fold, P&lt;0.01) and p16 (3-fold), SASP proteins CXCL-8 (6-fold, P&lt;0.05) and IL-6 (8-fold) as well as ̴ 75% reduction in expression of <i>SIRT1</i> and <i>SIRT6</i> (P&lt;0.05) (n=5). Metformin treatment reduced H₂O₂ induced IL-6 ( ̴ 74%, P&lt;0.05), CXCL-8 ( ̴ 88%, P&lt;0.05) and p16 ( ̴ 61%), with increased expression of <i>SIRT1</i> (3-fold, P&lt;0.05) and <i>SIRT6</i> (3-fold) (n=5). At the protein level (n=4), H₂O₂ increased p21 (18-fold, P&lt;0.05) and p16 (3-fold) but decreased SIRT6 ( ̴ 56%, P&lt;0.05). Metformin treatment inhibited p16 ( ̴ 67%) and p21 ( ̴ 77%) induction, whilst increasing sirtuin-6 (2-fold). <b>Conclusion:</b> These data suggest that metformin reverses oxidative stress-induced suppression of sirtuin-1/6 at both the mRNA and protein level, thereby modulating senescence markers. Metformin maybe beneficial in treating accelerated aging in COPD patients.

SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.