Publications

Volumetric intravascular ultrasound (IVUS) analysis is currently performed at a fixed frame interval, neglecting the cyclic changes in vessel dimensions occurring during the cardiac cycle that can affect the reproducibility of the results. Analysis of end-diastolic (ED) IVUS frames has been proposed to overcome this limitation. However, at present, there is lack of data to support its superiority over conventional IVUS.The present study aims to compare the reproducibility of IVUS volumetric analysis performed at a fixed frame interval and at the ED frames, identified retrospectively using a novel deep-learning methodology.IVUS data acquired from 97 vessels were included in the present study; each vessel was segmented at 1 mm interval (conventional approach) and at ED frame twice by an expert analyst. Reproducibility was tested for the following metrics; normalized lumen, vessel and total atheroma volume (TAV), and percent atheroma volume (PAV).The mean length of the analyzed segments was 50.0 ± 24.1 mm. ED analysis was more reproducible than the conventional analysis for the normalized lumen (mean difference: 0.76 ± 4.03 mm3 vs. 1.72 ± 11.37 mm3 ; p for the variance of differences ratio < 0.001), vessel (0.30 ± 1.79 mm3 vs. -0.47 ± 10.26 mm3 ; p < 0.001), TAV (-0.46 ± 4.03 mm3 vs. -2.19 ± 14.39 mm3 ; p < 0.001) and PAV (-0.12 ± 0.59% vs. -0.34 ± 1.34%; p < 0.001). Results were similar when the analysis focused on the 10 mm most diseased segment. The superiority of the ED approach was due to a more reproducible detection of the segment of interest and to the fact that it was not susceptible to the longitudinal motion of the IVUS probe and the cyclic changes in vessel dimensions during the cardiac cycle.ED IVUS segmentation enables more reproducible volumetric analysis and quantification of TAV and PAV that are established end points in longitudinal studies assessing the efficacy of novel pharmacotherapies. Therefore, it should be preferred over conventional IVUS analysis as its higher reproducibility is expected to have an impact on the sample size calculation for the primary end point.

. Objective. Emotional distress has been related to clinical events in patients with coronary artery disease, but the influence of positive affect (i.e. mood states such as activity, joy and cheerfulness) has received little attention. Therefore, we wanted to investigate the role of positive affect on clinical outcome after percutaneous coronary intervention (PCI) with stent implantation in these patients. Design. Prospective follow‐up study. At baseline, patients from the Rapamycin‐Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry completed measures of positive affect, depression and anxiety post‐PCI. Patients with reduced positive affect scored 1 SD below the mean score. Setting. University Hospital; Thoraxcenter of the Department of Cardiology. Subjects. 874 patients (72% men; 62.2 ± 10.9 years) from the RESEARCH registry. Main outcome measure. Death or myocardial infarction (MI) 2 years post‐PCI. Results. At follow‐up, there were 52 clinical events (deaths n = 27, MIs n = 25). Reduced positive affect and depression/anxiety were associated with poor prognosis, but reduced positive affect was the only independent predictor of events. The incidence of death/MI in adequate versus reduced positive affect patients was 4% (29/663) vs. 11% (23/211); HR = 2.55 (95% CI 1.46–4.34, P = 0.001), adjusting for clinical variables. Reduced positive affect and diabetes were independent prognostic factors, and patients with one (HR = 2.84, 95% CI 1.58–5.10) or both (HR = 5.61, 95% CI 2.25–13.99) of these factors had a higher risk when compared with nondiabetic patients with adequate positive affect, P ≤ 0.003. Conclusions. Reduced positive affect independently predicted death/MI following stent implantation, and improved risk stratification above and beyond diabetes.

The plasma membrane of airway smooth muscle contains a high density of K+ channels of various types that mainly regulate membrane potential. To examine whether these K+ channels are involved in bronchodilating mechanisms in human airways, relaxation concentration-response studies to isoproterenol, theophylline, and a K(+)-channel opener, lemakalim (BRL 38227), were obtained in the presence or absence of charybdotoxin (ChTX) (10 or 100 nM), an inhibitor of large conductance Ca(2+)-activated K+ channels (KCa) in smooth muscle. The effects of other potassium channel blockers, apamin (0.1 microM, a small-conductance KCa blocker) and BRL 31660 (10 microM, an ATP-sensitive K(+)-channel blocker) on isoproterenol-induced bronchodilation were also examined. All relaxation studies were performed on spontaneous tone and in the presence of 1 microM indomethacin. ChTX produced a dose-dependent significant rightward shift in the isoproterenol relaxation response curves without changing maximum relaxation; geometric mean values of EC50 were 4.6 nM without and 19 nM with 10 nM ChTX (n = 7, p less than 0.005), and 3.4 nM without and 41 nM with 100 nM ChTX (n = 4, p less than 0.05), respectively. The theophylline relaxation responses were inhibited to a lesser extent by ChTX (10 nM) (ED50 of 32 microM without and 71 microM with ChTX, n = 7, p less than 0.05), whereas lemakalim-induced relaxation response was not affected. Other K(+)-channel blockers, apamin and BRL31660, failed to affect isoproterenol-induced bronchodilation. These results suggest that ChTX-sensitive K+ channels are involved in bronchodilation induced by beta-agonists and theophylline in human airways.

Protein kinase (PK) C is an increasingly diverse family of enzymes that has been implicated in a range of cellular functions within the eosinophil. Using isoform-specific polyclonal antibodies, we have explored the expression of PKC isoforms in circulating eosinophils. Initial studies demonstrated the presence of the alpha, betaI, betaII, and zeta and the low-level expression of the delta, epsilon, iota, and micro isoforms but no detectable expression of the gamma, eta, and theta isoforms in both normal and asthmatic subjects. There was no difference in the total protein expression between these two groups. Subsequent studies examined the expression and activation of PKC isoforms in circulating eosinophils from asthmatic patients before and 24 h after a late asthmatic response to an inhaled allergen. Cellular fractionation showed PKC-alpha and PKC-betaII to be mainly located in the cytosol, whereas PKC-betaI was constitutively more expressed in the membrane. No changes in expression or subcellular localization of these isoforms were seen after allergen challenge. In contrast, PKC-zeta expression was increased after allergen challenge, and we demonstrated a significant PKC-zeta translocation to the membrane, in keeping with activation of the enzyme. Our results suggest that 24 h after allergen exposure of asthmatic patients, there is increased expression and activation of eosinophil PKC-zeta that correlates with late asthmatic responses recorded between 4 and 10 h postallergen challenge.

The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted.

To investigate the relationship between isoniazid resistance and HIV infection in patients with tuberculosis, the authors evaluated data in the Los Angeles County tuberculosis registry on 1,506 patients for whom drug susceptibility results were available.

Background: Clinical implications of online 3-dimensional optical frequency domain imaging (3D-OFDI)-guided stenting for bifurcation lesions have not been investigated in the randomized controlled trials. The purpose of this study was to determine whether online 3D-OFDI-guided stenting is superior to angiography-guided percutaneous coronary intervention (PCI) in terms of incomplete stent apposition at the bifurcation segment. Methods: The OPTIMUM trial (Online 3-Dimensional Optical Frequency Domain Imaging to Optimize Bifurcation Stenting Using UltiMaster Stent) was a randomized, multicenter clinical trial. Eligible patients had an angiographically significant stenosis in the bifurcation lesion treated with a provisional single stent strategy using the Ultimaster sirolimus eluting stent. Patients were randomly allocated to either online 3D-OFDI-guided or angiography-guided PCI. Patients randomized to 3D-OFDI guidance underwent online 3D-OFDI assessment after rewiring into the jailed side branch after stenting and proximal optimization technique, while in the angiography guidance arm, rewiring was performed using conventional fluoroscopic/angiographic guidance. The primary end point of this trial was the postprocedural average percentage of malapposed struts per lesion assessed by OFDI in the confluence zone of the main and side branches. Results: Between June 8, 2017 and September 26, 2018, 110 patients with 111 bifurcation lesions were randomized at 4 Japanese centers. Of these, 56 patients with 57 lesions were treated with 3D-OFDI-guided PCI, whereas 54 patients with 54 lesions were treated with angiography-guided PCI. In the 3D-OFDI guidance arm, the feasibility of online 3D-OFDI was 98.2%. The average percentage of incomplete stent apposition per lesion at bifurcation was lower in the 3D-OFDI guidance arm than that in the angiography guidance arm (19.5±15.8% versus 27.5±14.2%, P =0.008). The superiority of the 3D-OFDI guidance arm was also confirmed in the strut level analysis (odds ratio: 0.54 [95% CI, 0.36–0.81]; P =0.003). Conclusions: Online 3D-OFDI-guided bifurcation PCI was superior to angiography-guided bifurcation PCI in terms of acute incomplete stent apposition at bifurcation. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02972489.

A novel approach for the treatment of acute complications and the prevention of restenosis after percutaneous transluminal angioplasty may be the placement of endovascular prostheses (stents). Stents constructed of metal have proven to be thrombogenic, and although they show a tendency to reduce restenosis, they do not prevent it. Pursuant to the search for stents with improved material and surface characteristics, we report in this paper the histological results obtained with a synthetic polymer (polyethylene terephthalate) stent after placement in porcine peripheral arteries. Eight stents were placed at a preselected site and resulted in a 87.5% angiographic patency rate at four weeks' follow-up examination. The neointima measured 114 ± 38 μm (mean ± SEM) on top of the fibers and 246 ± 44 μm between the fibers. Medial impression by the stent measured 27% ± 5%. The neointima consisted mainly of smooth muscle cells. A variable inflammatory reaction and foreign body response to the polymer was observed in all vessels. The present study shows the feasibility of the arterial implantation of polymer stents, in that they result in good intermediate-term arterial patency and limited neointimal hyperplasia. The observed inflammatory reaction, if prolonged, may limit the use of this polymer stent.

Incidence, associated risk factors and impact on mortality of infections after bypass surgery (CABG) and stenting (PCI) for multivessel coronary disease (MVD) have never been reported in a large randomised trial. The aim of the present study was to evaluate, in patients with MVD, the prevalence of major infections after PCI and CABG and to assess their impact on mortality.The SYNTAX trial randomised 1,800 MVD patients to either CABG or PCI. Patients were followed up to five years. The primary endpoint of this post hoc analysis was the occurrence of major infection. At five years of follow-up, the primary endpoint had occurred in 142 (15.8%) patients in the CABG arm and 44 (4.9%) patients in the PCI arm (≤60 days HR - 7.9, 95% CI: 4.7 to 13.1; p<0.001) (>60 days - HR 0.79, 95% CI: 0.44 to 1.44; p=0.45). Major infections were independently associated with a higher risk of all-cause mortality at five years (adjusted HR 2.6, 95% CI: 1.8 to 3.8, p<0.001).CABG is associated with a higher incidence of post-procedure major infections compared to PCI. Major infections are independently associated with all-cause mortality.

In human airways synthetic human sequence calcitonin gene‐related peptide (hCGRP), a novel peptide produced by alternative processing of mRNA from the calcitonin gene, caused concentration‐dependent contraction of human bronchi (EC 50 4.9 × 10 −9 m ) and was significantly more potent than substance P or carbachol. The contractile response was unaffected by atropine (2 × 10 −6 m ), propranolol (10 −6 m ), indomethacin (10 −5 m ), tetrodotoxin (3 × 10 −6 m ), chlorpheniramine (10 −4 m ), cimetidine (10 −5 m ), or FPL55712 (10 −4 m ) suggesting a direct effect of CGRP on airways smooth muscle. CGRP was detected in human airways by radioimmunoassay with highest concentrations in cartilaginous airways. CGRP was localised by immunocytochemistry to both nerves and ganglia in human airways. CGRP, is a potent constrictor of human airways and may have important effects on airway function and be implicated in the pathogenesis of bronchial hyper‐responsiveness and asthma.