Publications

The effects of zaprinast (M&B 22948), a selective guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor, and sodium nitroprusside on cyclic GMP content, phosphoinositide hydrolysis and airway smooth muscle tone were examined in flurbiprofen pretreated bovine tracheal smooth muscle (BTSM). Anion‐exchange chromatography of the soluble fraction of BTSM homogenates resolved three peaks of Ca 2+ /calmodulin‐independent phosphodiesterase (PDE) activity that corresponded to type la (cyclic GMP‐specific, zaprinast‐inhibitable), type II (cyclic GMP‐stimulated) and type IV (Ro 20 1724‐inhibitable) PDE isoenzymes. Zaprinast caused a selective inhibition of the type Ia PDE isoenzyme (IC 50 0.94 μ m ) with respect to the type II and IV (IC 50 s 93 μ m and 197 μ m respectively) isoenzymes. Pretreatment of BTSM strips with zaprinast (10 μ m ) for 20min affected neither the initial rate of force development, nor the resultant magnitude of contraction induced by methacholine (10 μ m ). In addition, zaprinast (10 μ m ; 20 min) did not affect the cumulative concentration‐response relationship induced by methacholine. In contrast, sodium nitroprusside (300 μ m ) either alone, or in combination with zaprinast (10 μ m ), significantly attenuated tone induced by low, but not high concentrations of methacholine. This resulted in a non‐parallel, rightwards shift of the methacholine concentration‐response curves (nitroprusside: 4.0 fold; nitroprusside/zaprinast: 4.8 fold at the EC 50 values), without a reduction in the maximum tone generated. In BTSM slices, zaprinast (10 or 100 μ m ) did not influence basal or methacholine (10 μ m )‐stimulated cyclic GMP accumulation or inositol 1,4,5‐trisphosphate (Ins(1,4,5)P 3 ) mass accumulation over a 60s incubation period, although it did significantly increase cyclic GMP content over longer (30 min) stimulation periods. In [ 3 H]‐inositol prelabelled BTSM slices, stimulated in the presence of 5 m m LiCl, methacholine (10 μ m ) caused a marked increase in total [ 3 H]‐inositol phosphate accumulation. This effect was not inhibited by zaprinast (10 μ m ), sodium nitroprusside (300 μ m ) or a combination of these drugs despite these agents markedly increasing tissue cyclic GMP content. These findings demonstrate that despite zaprinast being a potent and selective inhibitor of the type Ia PDE isoenzyme in a cell‐free system, this drug only increases cyclic GMP content in BTSM following prolonged agonist‐stimulation. This may explain its lack of inhibitory effect on methacholine‐induced tone. The inability of drugs which increase tissue cyclic GMP content and exhibit anti‐spasmogenic activity to inhibit methacholine‐stimulated Ins(1,4,5)P 3 formation suggests that, unlike vascular smooth muscle, cyclic GMP‐dependent mechanisms do not regulate receptor‐mediated phosphoinositide hydrolysis in BTSM.

The stent is currently taking the lead in the treatment of obstructive coronary artery disease. The interest in this device is not only reflected by the relative number of patients referred for angioplasty and treated with a stent but also by the large number of clinical trials. These can be divided into trials assessing the safety and feasibility of the implantation of second generation or new stents, studies assessing novel treatment strategies and randomized clinical trials. With respect to the latter, they all compare stent implantation with balloon angioplasty. Of major importance will be the comparison of stent implantation with surgical revascularization of obstructive coronary artery disease. The increasing number of therapeutic options, however, confront the physician with the difficult choice and responsibility of selecting the most appropriate treatment. Therefore, systematic and objective evaluation of the available therapeutic approaches by means of appropriately designed trials is imperative. The purpose of this paper is to summarize and to put into perspective the various studies on intracoronary stenting. Distinction is made between observational studies testing a device or evaluating a new concept in intracoronary stenting and randomized clinical trials.

<title>Abstract</title> Viral infection due to severe acute respiratory syndrome coronavirus 2 (<bold>SARS-CoV-2</bold>) induce a dynamic immune environment. Using nasal mucosal samples in 139 participants from the STOIC study (community-based randomised clinical trial for the use of budesonide in early onset SARS-CoV-2, NCT04416399), we applied predefined immune mediator nodes in relation to clinical outcomes and viral burden. Interferon- and chemokine-dominant nodes increased expression as compared to health, validating our modular approach. Next, we demonstrated that an increase in mucosal immunity-like node consisting of CCL13, CCL17, IL-33, among others was associated with a mean 3.7-day quicker recovery with no primary outcome events, irrespective of treatment arm. By day 14 the mucosal node divided into two daughter nodes linked to interferon molecules and was transcriptionally detectable in nasal cavity basal, hillock and ciliated cells (as per public single cell dataset EGAD00001007718). Our data suggest mucosal-associated mediators are key for early symptom resolution of SARS-CoV-2.

Abstract Background Exhaled breath volatile organic compound (VOC) analysis for airway disease monitoring is promising. However, contrary to nitric oxide the method for exhaled breath collection has not yet been standardized and the effects of expiratory flow and breath-hold have not been sufficiently studied. These manoeuvres may also reveal the origin of exhaled compounds. Methods 15 healthy volunteers (34 ± 7 years) participated in the study. Subjects inhaled through their nose and exhaled immediately at two different flows (5 L/min and 10 L/min) into methylated polyethylene bags. In addition, the effect of a 20 s breath-hold following inhalation to total lung capacity was studied. The samples were analyzed for ethanol and acetone levels immediately using proton-transfer-reaction mass-spectrometer (PTR-MS, Logan Research, UK). Results Ethanol levels were negatively affected by expiratory flow rate (232.70 ± 33.50 ppb vs. 202.30 ± 27.28 ppb at 5 L/min and 10 L/min, respectively, p &lt; 0.05), but remained unchanged following the breath hold (242.50 ± 34.53 vs. 237.90 ± 35.86 ppb, without and with breath hold, respectively, p = 0.11). On the contrary, acetone levels were increased following breath hold (1.50 ± 0.18 ppm) compared to the baseline levels (1.38 ± 0.15 ppm), but were not affected by expiratory flow (1.40 ± 0.14 ppm vs. 1.49 ± 0.14 ppm, 5 L/min vs. 10 L/min, respectively, p = 0.14). The diet had no significant effects on the gasses levels which showed good inter and intra session reproducibility. Conclusions Exhalation parameters such as expiratory flow and breath-hold may affect VOC levels significantly; therefore standardisation of exhaled VOC measurements is mandatory. Our preliminary results suggest a different origin in the respiratory tract for these two gasses.

Intracoronary ultrasound (ICUS) provides valuable information on the distribution and composition of atherosclerotic plaque. For this reason its use for guidance of interventional procedures has been advocated. Recently, on-line systems of three-dimensional reconstruction have been introduced and offer great potential for guidance of interventional procedures since valuable details on longitudinal architecture of the plaque under treatment are obtained. In this article we review the current clinical application of three-dimensional (3-D) ICUS and report our experience with the use of an on-line 3-D ICUS system for guidance of interventional procedures. In our experience 3-D reconstruction of ICUS proved to be a feasible method facilitating device selection and guidance of catheter based interventions.

The SYNTAX trial demonstrated negative impact of repeat revascularization (RR) on 5-year outcomes following PCI/CABG in patients with three-vessel(3VD) and/or left main coronary artery disease(LMCAD). We aimed to investigate the impact of RR within 5 years, on 10-year mortality in patients with 3VD and/or LMCAD after PCI/CABG.The SYNTAXES study evaluated the vital status out to 10 years of patients with 3VD and/or LMCAD. Patients were stratified by RR within 5 years and randomized treatment. The association between RR within 5 years and 10-year mortality was assessed.A total of 330 out of 1800 patients (18.3%) underwent RR within 5 years. RR occurred more frequently after initial PCI than after initial CABG (25.9% vs. 13.7%, p < 0.001). Overall, 10-year mortality was comparable between patients undergoing RR and those not (28.2% vs. 26.1%, adjusted HR: 1.17, 95%CI 0.93-1.48, p = 0.187). In the PCI arm, RR was associated with a trend toward higher 10-year mortality (adjusted HR: 1.29, 95%CI 0.97-1.72, p = 0.075), while in the CABG arm, the trend was opposite (adjusted HR: 0.74, 95%CI 0.46-1.20, p = 0.219). Among patients requiring RR, those who underwent PCI as initial revascularization had a higher risk of 10-year mortality compared to initial CABG (33.5% vs. 17.6%, adjusted HR: 2.09, 95%CI 1.21-3.61, p = 0.008).In the SYNTAXES study, RR within 5 years had no impact on 10-year all-cause death in the population overall. Among patients requiring any repeat procedures, 10-year mortality was higher after initial treatment with PCI than after CABG. These exploratory findings should be investigated with larger populations in future studies.URL: https://www.gov ; SYNTAXES Unique identifier: NCT03417050. URL: https://www.gov ; SYNTAX Unique identifier: NCT00114972.

No abstract is provided for this article.

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Acute coronary artery occlusion occurs in 2 to 11% of the patients who undergo coronary angioplasty and is the major cause of in-hospital mortality and morbidity associated with coronary angioplasty.1–4 This procedural complication is usually caused by an occlusive dissection in association with thrombosis, spasm and elastic recoil. If immediate redilatation is unsuccessful, emergency surgery is traditionally recommended, but because of the clinical instability of these ischemic patients, acute surgery is associated with high perioperative mortality and morbidity, and despite emergent revascularization, development of myocardial infarction cannot be prevented in a substantial number of patients.5 New methods that can restore anterograde flow and effectively stabilize the clinical condition after refractory acute occlusion are highly desirable. They may serve as a safe bridge until subsequent surgery or may even serve as an alternative to surgery. Emergency stent implantation in the dissected segment has been shown to restore anterograde flow.6,7 However, because the first generation of stents had a high tendency to acute thrombotic occlusion, it was decided that emergency stent implantation should be followed by “semi-elective” surgery. This study reports the acute results of the management of acute coronary artery occlusion refractory to redilation with emergency stent implantation followed by “semi-elective” bypass surgery in most of these patients.

Aims: This study aimed to compare the acute expansion behaviour of a polymer-based bioresorbable scaffold and a second-generation metallic DES platform in a realistic coronary artery lesion model.Experimental mechanical data with conventional methods have so far shown little difference between metallic stents and currently available polymer-based bioresorbable scaffolds (BRS).Nevertheless, differences in acute results have been observed in clinical studies comparing BRS directly with metallic DES platforms. Methods and results:We examined the expansion behaviour of the bioresorbable vascular scaffold (3.0×18 mm Absorb BVS; Abbott Vascular, Santa Clara, CA, USA) and a metallic DES (3.0×18 mm XIENCE Prime; Abbott Vascular) after expansion at 37°C using identical coronary artery stenosis models (in total 12 experiments were performed).Device expansion was compared during balloon inflation and after deflation using microscopy to allow assessment of plaque recoil.Minimal lumen diameter (MLD) and minimal lumen area (MLA) and stent eccentricity were quantified from optical coherence tomography (OCT) imaging at nominal diameter and after post-dilation at 18 atm.The MLA in the models with BVS deployed was 4.92±0.17mm² while in the metallic DES it was 5.40±0.13mm 2 (p=0.02) at nominal pressure (NP), and 5.41±0.20 and 6.07±0.25 mm 2 (p=0.02),respectively, after expansion at 18 atm.Stent eccentricity index at the MLA was 0.71±0.02 in BVS compared to 0.81±0.02 in the metal stent at NP (p=0.004), and 0.73±0.03compared to 0.75±0.02at 18 atm (p=0.39).Conclusions: Results obtained in this in vitro lesion model were comparable to the results in randomised clinical trials comparing BVS and XIENCE stents in vivo.Such models may be useful in future BRS developments to predict their acute response in vivo in eccentric lesions.