COPD Wetenschap

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart.
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Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart.

Toxicol Appl Pharmacol. 2019 Oct 13;:114778

Authors: Cassambai S, Mee CJ, Renshaw D, Hussain A

Abstract
BACKGROUND AND PURPOSE: Tiotropium bromide (TB) is a long acting muscarinic receptor antagonist used to manage chronic obstructive pulmonary disease (COPD). Recent meta-analyses suggest an increased risk of cardiovascular events with TB. Ca2+/calmodulin dependent kinase II (CaMKII) and L-type Ca2+ channels regulate Ca2+ concentrations allowing management of Ca2+ across membranes, however pathological increases are initially slow and progressive but once the cytosolic concentration rises >1-3 μM from ~100 nM, calcium overload occurs and can lead to cell death. Ipratropium bromide, a short acting muscarinic receptor antagonist has previously been found to induce Ca2+ mediated eryptosis. The aim of this study was to investigate the role of Ca2+ in Tiotropium bromide mediated cardiotoxicity.
EXPERIMENTAL APPROACH: Isolated Sprague-Dawley rat hearts were perfused with TB (10-0.1 nM) ± KN-93 (400 nM) or nifedipine (1 nM). Hearts were stained to determine infarct size (%) using triphenyltetrazolium chloride (TTC), or snap frozen to determine p-CaMKII (Thr286) expression. Cardiomyocytes were isolated using a modified Langendorff perfusion and enzymatic dissociation before preparation for Fluo 3-AM staining and flow cytometric analysis.
KEY RESULTS: TB increased infarct size compared with controls by 6.91-8.41%, with no effect on haemodynamic function. KN-93/nifedipine with TB showed a 5.90/7.38% decrease in infarct size compared to TB alone, the combined use of KN-93 with TB also showed a significant increase in left ventricular developed pressure whilst nifedipine with TB showed a significant decrease in coronary flow. TB showed a 42.73% increase in p-CaMKII (Thr286) versus control, and increased Ca2+ fluorescence by 30.63% in cardiomyocytes.
CONCLUSIONS AND IMPLICATIONS: To our knowledge, this is the first pre-clinical study to show that Tiotropium bromide induces Ca2+ signalling via CaMKII and L-type Ca2+ channels to result in cell damage. This has significant clinical impact due to long term use of TB in COPD patients, and warrants assessment of cardiac drug safety.

PMID: 31618660 [PubMed - as supplied by publisher]



Discordance between old and new criteria for stratifying patients with COPD.
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Discordance between old and new criteria for stratifying patients with COPD.

J Bras Pneumol. 2019 Oct 14;45(6):e20190183

Authors: Araújo AMSD, Teixeira P, Hespanhol V, Correia-de-Sousa J

PMID: 31618300 [PubMed - in process]



Effects of a high-intensity pulmonary rehabilitation program on the minute ventilation/carbon dioxide output slope during exercise in a cohort of patients with COPD undergoing lung resection for non-small cell lung cancer.
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Effects of a high-intensity pulmonary rehabilitation program on the minute ventilation/carbon dioxide output slope during exercise in a cohort of patients with COPD undergoing lung resection for non-small cell lung cancer.

J Bras Pneumol. 2019;45(6):e20180132

Authors: Perrotta F, Cennamo A, Cerqua FS, Stefanelli F, Bianco A, Musella S, Rispoli M, Salvi R, Meoli I

Abstract
OBJECTIVE: Preoperative functional evaluation is central to optimizing the identification of patients with non-small cell lung cancer (NSCLC) who are candidates for surgery. The minute ventilation/carbon dioxide output (VE/VCO2) slope has proven to be a predictor of surgical complications and mortality. Pulmonary rehabilitation programs (PRPs) could influence short-term outcomes in patients with COPD undergoing lung resection. Our objective was to evaluate the effects of a PRP on the VE/VCO2 slope in a cohort of patients with COPD undergoing lung resection for NSCLC.
METHODS: We retrospectively evaluated 25 consecutive patients with COPD participating in a three-week high-intensity PRP prior to undergoing lung surgery for NSCLC, between December of 2015 and January of 2017. Patients underwent complete functional assessment, including spirometry, DLCO measurement, and cardiopulmonary exercise testing.
RESULTS: There were no significant differences between the mean pre- and post-PRP values (% of predicted) for FEV1 (61.5 ± 22.0% vs. 62.0 ± 21.1%) and DLCO (67.2 ± 18.1% vs. 67.5 ± 13.2%). Conversely, there were significant improvements in the mean peak oxygen uptake (from 14.7 ± 2.5 to 18.2 ± 2.7 mL/kg per min; p < 0.001) and VE/VCO2 slope (from 32.0 ± 2.8 to 30.1 ± 4.0; p < 0.01).
CONCLUSIONS: Our results indicate that a high-intensity PRP can improve ventilatory efficiency in patients with COPD undergoing lung resection for NSCLC. Further comprehensive prospective studies are required to corroborate these preliminary results.

PMID: 31618297 [PubMed - in process]



AHRR Methylation is a Significant Predictor of Mortality Risk in Framingham Heart Study.
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AHRR Methylation is a Significant Predictor of Mortality Risk in Framingham Heart Study.

J Insur Med. 2019 Oct 16;:

Authors: Philibert RA, Dogan MV, Mills JA, Long JD

Abstract
Background.-The ability to predict mortality is useful to clinicians, policy makers and insurers. At the current time, prediction of future mortality is still an inexact process with some proposing that epigenetic assessments could play a role in improving prognostics. In past work, we and others have shown that DNA methylation status at cg05575921, a well-studied measure of smoking intensity, is also a predictor of mortality. However, the exact extent of that predictive capacity and its independence of other commonly measured mortality risk factors are unknown. Objective.-To determine the capacity of methylation to predict mortality. Method.-We analyzed the relationship of methylation at cg05575921 and cg04987734, a recently described quantitative marker of heavy alcohol consumption, to mortality in the Offspring Cohort of the Framingham Heart Study using proportional hazards survival analysis. Results.-In this group of participants (n = 2278) whose average age was 66 ± 9 years, we found that the inclusion of both cg05575921 and cg04987734 methylation to a base model consisting of age and sex only, or to a model containing 11 commonly used mortality risk factors, improved risk prediction. What is more, prediction accuracy for the base model plus methylation data was increased compared to the base model plus known predictors of mortality (CHD, COPD, or stroke). Conclusion.-Cg05575921, and to a smaller extent cg04987734, are strong predictors of mortality risk in older Americans and that incorporation of DNA methylation assessments to these and other loci may be useful to population scientists, actuaries and policymakers to better understand the relationship of environmental risk factors, such as smoking and drinking, to mortality.

PMID: 31618096 [PubMed - as supplied by publisher]



CT-based Airway Flow Model to Assess Ventilation in Chronic Obstructive Pulmonary Disease: A Pilot Study.
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CT-based Airway Flow Model to Assess Ventilation in Chronic Obstructive Pulmonary Disease: A Pilot Study.

Radiology. 2019 Oct 15;:190395

Authors: Kim M, Doganay O, Matin TN, Povey T, Gleeson FV

Abstract
Background The lack of functional information in thoracic CT remains a limitation of its use in the clinical management of chronic obstructive pulmonary disease (COPD). Purpose To compare the distribution of pulmonary ventilation assessed by a CT-based full-scale airway network (FAN) flow model with hyperpolarized xenon 129 (129Xe) MRI (hereafter, 129Xe MRI) and technetium 99m-diethylenetriaminepentaacetic acid aerosol SPECT ventilation imaging (hereafter, V-SPECT) in participants with COPD. Materials and Methods In this prospective study performed between May and August 2017, pulmonary ventilation in participants with COPD was computed by using the FAN flow model. The modeled pulmonary ventilation was compared with functional imaging data from breath-hold time-series 129Xe MRI and V-SPECT. FAN-derived ventilation images on the coronal plane and volumes of interest were compared with functional lung images. Percentage lobar ventilation estimated by the FAN model was compared with that measured at 129Xe MRI and V-SPECT. The statistical significance of ventilation distribution between FAN and functional images was demonstrated with the Spearman correlation coefficient and χ2 distance. Results For this study, nine participants (seven men [mean age, 65 years ± 5 {standard deviation}] and two women [mean age, 63 years ± 7]) with COPD that was Global Initiative for Chronic Obstructive Lung Disease stage II-IV were enrolled. FAN-modeled ventilation profile showed strong positive correlation with images from 129Xe MRI (ρ = 0.67; P < .001) and V-SPECT (ρ = 0.65; P < .001). The χ2 distances of the ventilation histograms in the volumes of interest between the FAN and 129Xe MRI and FAN and V-SPECT were 0.16 ± 0.08 and 0.28 ± 0.14, respectively. The ratios of lobar ventilations in the models were linearly correlated to images from 129Xe MRI (ρ = 0.67; P < .001) and V-SPECT (ρ = 0.59; P < .001). Conclusion A CT-based full-scale airway network flow model provided regional pulmonary ventilation information for chronic obstructive pulmonary disease and correlates with hyperpolarized xenon 129 MRI and technetium 99m-diethylenetriaminepentaacetic acid aerosol SPECT ventilation imaging. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Schiebler and Parraga in this issue.

PMID: 31617794 [PubMed - as supplied by publisher]



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