Publications

Rationale: There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.Objectives: To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke–induced glucocorticoid insensitivity.Methods: Wild-type, PI3Kγ knock-out and PI3Kδ kinase dead knock-in transgenic mice were used in a model of cigarette smoke–induced glucocorticoid insensitivity. Peripheral lung tissue was obtained from six healthy nonsmokers, nine smokers with normal lung function, and eight patients with COPD.Measurements and Main Results: In vitro oxidative stress activates PI3K and induced a relative glucocorticoid resistance, which is restored by PI3K inhibition. In vivo, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced histone deacetylase 2 activity and reduced glucocorticoid function. Histone deacetylase 2 activity and the antiinflammatory effects of glucocorticoids were restored in PI3Kδ kinase dead knock-in but not PI3Kγ knock-out smoke-exposed mice compared with wild type mice, correlating with reduced histone deacetylase 2 tyrosine nitration. Glucocorticoid receptor expression was significantly reduced in smoke-exposed mice, in smokers with normal lung function, and in patients with COPD.Conclusions: These data show that therapeutic inhibition of PI3Kδ may restore glucocorticoid function in oxidative stress–induced glucocorticoid insensitivity.

Rupture of vulnerable plaques is the main cause of acute coronary syndrome and myocardial infarction. Identification of vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize such plaques. Several diagnostic methods are currently tested to detect vulnerable plaques. Angiography has a low discriminatory power to identify the vulnerable plaque, but does provide information about the entire coronary tree and serves as guide for invasive imaging techniques and therapy. Angioscopy offers a direct visualization of the plaque surface and intra-luminal structures like thrombi and tears. However, angioscopy is difficult to perform, invasive and only the proximal part of the vessels can be investigated. IVUS (intravascular ultrasound) provides some insight into the composition of plaques. The detection of vulnerable plaques is mainly based on series of case reports with a lack of prospectivity and follow-up. Palpography, an IVUS derived technique, reveals information, which is not recognizable in IVUS. It can differentiate between deformable and non-deformable tissue, which enables the technique to detect vulnerable plaques with a positive predictive value. The clinical value of palpography is currently under investigation. Thermography assesses the temperature heterogeneity as an indicator of the metabolic state of the plaque. A coincidence of temperature rise and localization of vulnerable plaque was suggested. OCT (optical coherence tomography) can provide images with ultrahigh resolution utilizing the back-reflection of near-infrared light from optical interfaces in tissue. Drawbacks are the low penetration depth into tissue and the absorbance of light by blood. Raman spectroscopy can provide quantification about the molecular composition of the plaque. Long acquisition time, the low penetration depth and light absorbance by blood limit the performance of the technique. Another light emitting technique is NIR (near infrared spectroscopy), which identifies lipid loaded plaques and is tested currently in clinical trials. Non-invasive MRI (magnetic resonance imaging) and multislice spiral computed tomography (MSCT), with their excellent ability to identify lipid-rich tissue, have been utilized to characterize potentially vulnerable plaques foremost in non-moving structures like the carotid arteries. Due to the resolution of the techniques small plaque structure cannot be assessed. The role of non-invasive imaging in vulnerable plaque detection is currently under investigation. Several invasive and non-invasive techniques are currently under development to assess the vulnerable plaque. Most of the techniques show exiting features, but none have proven their value in an extensive in vivo validation and all have a lack of prospective data.

Little information is available on the specific role of alveolar macro- phages (AMs) in modulating local cellular reactions to inhaled allergens in atopic asthma. We investigated the influence of alveolar macrophages obtained by bronchoalve- olar lavage (BAL) on the proliferative responses of lavage and peripheral lympho- cytes from 12 patients with atopic asthma, 6 nonasthmatic symptomatic atopic subjects, and 6 nonatopic normal volunteers, in the context of in vitro exposure to relevant and nonrelevant allergens. Fresh nonadherent bronchoalveolar lavage cells from atopic asthmatic patients, depleted of alveolar macrophages, proliferated spontaneously more than nonad- herent bronchoalveolar lavage cells from normal subjects. Addition of autologous asthmatic alveolar macrophages reduced this endogenous activation. Asthmatic and normal alveolar macrophages also inhibited phytohaemagglutinin-stimulated proliferation of both autologous and allogeneic nonadherent peripheral blood mono- nuclear cells (PBMC). In contrast, autologous asthmatic alveolar macrophages induced strong proliferation of peripheral blood mononuclear cells when stimula- ted with allergen to which the patient was skin test and radio allergosorbent test (RAST) reactive; however, no response was seen with allergens to which the patient was insensitive. No such allergen-specific proliferation was seen with alveolar macrophages from nonasthmatic atopic subjects. These data support the presence of functionally-active alveolar macrophages within the airways of atopic asthmatic patients, that under normal stable condi- tions suppress the induction of peripheral blood mononuclear cell responses, and which only on contact with specific allergen appear to switch to inducer alveolar macrophages, with consequent peripheral blood mononuclear cell hyperactiva- tion.

No abstract is provided for this article.

AbstractAsthma typically worsens overnight. Although 24-hr variation in environmental conditions may contribute to the worsening of dyspnea at night, this does not fully explain day-night patterns of this disease. Circadian (about 24-hr) rhythms in bioprocesses which influence airways patency constitute major contributory factors. The nighttime exacerbation of asthma may represent the influence of circadian bioperiodicities in bronchial patency, airways hyperreactivity to acetylcholine, histamine and house dust, and altered levels of several plasma constituents such as Cortisol, epinephrine, histamine and cyclic AMP.Key Words: Nocturnal asthmacircadian rhythmbronchial patencyairways hyperreactivityCortisolsympathetic toneparasympathetic tonearachidonic acid metabolitesplasma histamineIgEgastric refluxairways coolingenvironmental allergens

Journal Article Long-term follow-up after attempted angioplasty of saphenous vein grafts: the Thoraxcenter experience 1981–1988 Get access B. J. MEESTER, B. J. MEESTER *Thoraxcenter, Erasmus UniversityRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar M. SAMSON, M. SAMSON Search for other works by this author on: Oxford Academic PubMed Google Scholar H. SURYAPRANATA, H. SURYAPRANATA *Thoraxcenter, Erasmus UniversityRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar G. BONSEL, G. BONSEL ‡Institute for Medical Technology Assessment, Erasmus UniversityRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar M. VAN DEN BRAND, M. VAN DEN BRAND *Thoraxcenter, Erasmus UniversityRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar P. J. DE FEYTER, P. J. DE FEYTER *Thoraxcenter, Erasmus UniversityRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar P. W. SERRUYS P. W. SERRUYS *Thoraxcenter, Erasmus UniversityRotterdam, The Netherlands Correspondence:Prof. P. W. Serruys, MD. PhD. Catheterization Laboratory, Thoraxcenter, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal, Volume 12, Issue 5, May 1991, Pages 648–653, https://doi.org/10.1093/oxfordjournals.eurheartj.a059955 Published: 01 May 1991 Article history Received: 25 April 1990 Revision received: 30 July 1990 Published: 01 May 1991

Products of the prostaglandin H synthase (PGHS) metabolic pathway are thought to play a role in the pathogenesis of asthma. We determined the level of expression of the constitutive (PGHS-1) and inducible (PGHS-2) isoforms of the enzyme in induced sputum and bronchial biopsies of patients with asthma, patients with chronic obstructive pulmonary disease (COPD), and unaffected control subjects by immunocyto- and immunohistochemistry. Immunoreactivity for PGHS-2 was significantly greater in the induced sputum of patients with asthma and patients with COPD compared with unaffected control subjects. The level of PGHS-2 was greater in asthma than in COPD. Immunoreactivity for PGHS-1 increased in cells in the induced sputum of patients with asthma and patients with COPD compared with that of unaffected control subjects. Immunostained cells included macrophages, eosinophils, and neutrophils. Greater PGHS-2 immunoreactivity was seen in the submucosal inflammatory infiltrate and in the airway epithelium of patients with asthma compared with unaffected control subjects. In summary, we demonstrate an induction of PGHS-2 in asthma, suggesting increased formation of prostanoids, which may contribute to the inflammatory process. Taha R, Olivenstein R, Utsumi T, Ernst P, Barnes PJ, Rodger IW, Giaid A. Prostaglandin H synthase 2 expression in airway cells from patients with asthma and chronic obstructive pulmonary disease.

For patients with moderate asthma and persistent symptoms, low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide produced similar benefits. Effects were achieved at theophylline concentrations below the recommended therapeutic range. The addition of low-dose theophylline to inhaled glucosteroid may be preferable to and cheaper than increasing the dose of inhaled glucosteroid.

To develop a clinical prediction rule based on 3D reconstruction of coronary arteries that would prospectively identify lesions that are difficult to cross and could benefit from magnetic navigation.The coronary anatomy of a cohort of 120 lesions that had undergone percutaneous coronary intervention (derivation set) was analysed using 3D reconstruction for vessel and lesion characteristics. The crossing time was the total clock time to reach a satisfactory distal position after leaving the guiding catheter. Multivariable logistic regression and linear shrinkage with bootstrapping were used to develop a clinical prediction rule that dichotomised cases into easy or difficult (prolonged crossing time). A value of 6 was the best cut-off value. This clinical prediction rule was applied to a second independent cohort of patients (validation set) where crossing time was measured. The bootstrapped c-statistic of the model was 0.82 indicating excellent discrimination.3D reconstruction helped to develop a simple, accurate clinical prediction rule to identify difficult cases for conventional wires and in whom magnetic navigation may be preferable.

Central MessageComplete revascularization of complex coronary artery disease can be planned without cine-angiography by combining CT with 3D holograms to predict the graft lengths needed for CABG.See Commentary on page XXX. Complete revascularization of complex coronary artery disease can be planned without cine-angiography by combining CT with 3D holograms to predict the graft lengths needed for CABG. See Commentary on page XXX. A 71-year-old man was referred for consideration of coronary revascularization on the background of stable coronary artery disease in the context of exertional and occasional rest angina. His medical history included hypertension, dyslipidemia, well-controlled human immunodeficiency virus infection, and spinal stenosis. Per Mount Sinai Morningside Hospital regulation, additional institutional review board approval was not required. The patient provided written informed consent for publication of study data. The patient was enrolled in the FASTTRACK CABG trial (NCT 04142021), which aims to assess the feasibility of CCTA and FFRCT to replace coronary angiography as CABG guidance. A coronary computed tomography angiogram (CCTA) with CT-fractional flow reserve (FFRCT) was performed to plan revascularization and showed functionally significant triple-vessel coronary artery disease. There were respective fibrocalcific lesions and soft plaque in the proximal and distal parts of the right coronary artery. There were also significant fibrocalcific lesions in the left main stem, left anterior descending artery (LAD), LAD-first diagonal (D1) bifurcation, left circumflex artery, and ramus intermedius. Mixed plaques were found in the first obtuse marginal branch (OM1), with soft plaques in the distal LAD, D1, and OM1. Both anatomical and functional SYNTAX scores were 66.1Serres P.W. Onuma Y. Garg S. Sarno G. van den Brand M. Kappetein A.P. et al.Assessment of the SYNTAX score in the Syntax study.EuroIntervention. 2009; 5: 50-56Crossref Scopus (462) Google Scholar Thus, the heart team concluded that the patient should receive coronary artery bypass surgery (CABG). The patient was enrolled in the FASTTRACK CABG trial (NCT 04142021), which aims to assess the feasibility of CCTA and FFRCT to replace coronary angiography as CABG guidance. A 3-dimensional (3D) hologram was reconstructed from the CCTA, and preoperative measurements were performed to estimate the length of grafts needed to be harvested. The hologram reconstruction and measurements were performed using the CarnaLife Holo software (MedApp). The diameter of the right and left internal mammary arteries (RIMA, LIMA) and the distance from the internal mammary arteries to the corresponding coronary beds were measured. The distances between the LIMA to the D1 and the RIMA to the right coronary artery–posterior descending artery (PDA) were 38.6 mm and 88.5 mm, respectively. The predicted lengths for the radial artery (RA) grafts between the LAD and OM1 and the PDA and the left posterolateral artery were 57.3 mm and 51.9 mm, respectively (Figure 1, A and B; Video 1). Using this information for guidance, the patient underwent 5-vessel full-arterial, no-aortic touch, off-pump CABG via a median sternotomy with the following grafts: LIMA sequentially to D1 and LAD; RA as a T graft from LIMA to OM1; and RIMA–radial extension to PDA and left posterolateral. The hologram estimation of graft lengths ensured that only the left RA needed to be harvested (Figure 1, C and D). Assessment of transit time flow showed satisfactory flow in all grafts, with low pulsatility indexes. His postoperative course was uneventful; he was extubated on day 1 postoperatively and discharged home on day 4. At 30-day follow-up, he was angina-free, and repeated CCTA showed all grafts were patent, yielding a post-CABG SYNTAX score of 2.1Serres P.W. Onuma Y. Garg S. Sarno G. van den Brand M. Kappetein A.P. et al.Assessment of the SYNTAX score in the Syntax study.EuroIntervention. 2009; 5: 50-56Crossref Scopus (462) Google Scholar Another hologram was reconstructed using the post-CABG CTCA, and this showed the lengths of the RA grafts were 56.5 mm (LAD to OM1) and 53.1 mm (PDA to left posterolateral), which were similar to the pre-CABG estimations of 57.3 mm and 51.9 mm, respectively (Figure 1, E and F). A 3D-printing model was prepared for further evaluation (Figure 1, G and H). This is the first case to demonstrate that planning complex coronary revascularization can be achieved purely with CCTA, FFRCT, and 3D holograms. CCTA has the advantage of providing simultaneously an anatomic overview and plaque composition, which are both essential for risk stratification.2Serruys P.W. Hara H. Garg S. Kawashima H. Nørgaard B.L. Dweck M.R. et al.Coronary computed tomographic angiography for complete assessment of coronary artery disease: JACC State-of-the-Art review.J Am Coll Cardiol. 2021; 78: 713-736https://doi.org/10.1016/J.JACC.2021.06.019Crossref PubMed Scopus (0) Google Scholar Moreover, CCTA enables the distal lumen of total occlusions to be visualized, which helps identify targets for CABG.3Werner G.S. Use of coronary computed tomographic angiography to facilitate percutaneous coronary intervention of chronic total occlusions.Circ Cardiovasc Interv. 2019; 12e007387https://doi.org/10.1161/CIRCINTERVENTIONS.119.007387Crossref Scopus (9) Google Scholar FFRCT provides physiological assessment on top of anatomical information. However, the complex interaction between the stenosis of the native vessel and the grafts is still difficult to predict preoperatively. According to the SYNTAX III trial, functional assessment alters the decision of the heart team in more than 7% of cases and modifies the vessel for revascularization in 12% compared with CCTA alone.4Andreini D. Modolo R. Katagiri Y. Mushtaq S. Sonck J. Collet C. et al.Impact of fractional flow reserve derived from coronary computed tomography angiography on heart team treatment decision-making in patients with multivessel coronary artery disease: insights from the SYNTAX III REVOLUTION trial.Circ Cardiovasc Interv. 2019; 12e007607https://doi.org/10.1161/CIRCINTERVENTIONS.118.007607Crossref Scopus (60) Google Scholar The addition of 3D holograms can further empower surgeons to virtually visualize and manipulate complex anatomy by themselves before and during the actual operation.5Brun H. Bugge R.A.B. Suther L.K.R. Birkeland S. Kumar R. Pelanis E. et al.Mixed reality holograms for heart surgery planning: first user experience in congenital heart disease.Eur Heart J Cardiovasc Imaging. 2019; 20: 883-888https://doi.org/10.1093/EHJCI/JEY184Crossref PubMed Scopus (0) Google Scholar With contemporary software, they can plan the precise length of the grafts to be harvested, allowing them to make an individualized plan for their patient. This case demonstrates that visualization and measurements can be performed in real-time. It is important to emphasize that all measurements were performed with gestures and voice commands, allowing measurements without breaking sterility. This mixed-reality setting has the advantage of providing high-definition images while preserving situational awareness, which is ideal for surgeons. The current report showcases that it is safe and feasible to make complex and individualized revascularization plans without invasive coronary angiography entirely. Ultimately, it is the patient, who received expedited revascularization, was exposed to less radiation, and suffered from less tissue damage, who benefited the most from these technological advances. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJlNTk4YWFkYzIwMGFmOWU4NWNkOWE4MzljZGMwM2YzNyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjg4MjEwNTExfQ.gaYLkpBx9EGVWqZELy-wn3nixPb9Y598Gv0HAcXx3yUq6Ek-Fgxrpwbcen3LSUZmep0K8jm5yFK3q1t1LcLx9D2dsmbcAIsSkXAOKS5hOvtbF-5vG61MRACfgsVxPmYHHqwigPadSlGmH_gwLqWexWdiVPm11C9BLkOc3WWv7KZbFzN3DHayhinYxRMYeRI99_5TkUR6jym9MWn7j9Dq66TYc-P9m_dh7YJ_bvmNpPIXQnbX61np2RqnEVkqgUL-QUAdAM-VJ9JFlAG46M4WV0VzYn8leAtNKzw1w0qnjyAKOmztfOREnmdO_UaB5Q-BMabaA4MQpOi6dO_lE4pHOg Download .mp4 (58.22 MB) Help with .mp4 files Video 1This video shows the case information, the rationale for performing a 3-D hologram, and the final results of the analysis. Video available at: https://www.jtcvs.org/article/S2666-2507(23)00143-8/fulltext. Download .jpg (.39 MB) Help with files Video 1This video shows the case information, the rationale for performing a 3-D hologram, and the final results of the analysis. Video available at: https://www.jtcvs.org/article/S2666-2507(23)00143-8/fulltext.