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Amnon Ariel,1 Alan Altraja,2,3 Andrey Belevskiy,4 Piotr W Boros,5 Edvardas Danila,6 Matjaz Fležar,7 Vladimir Koblizek,8 Zvi G Fridlender,9 Kosta Kostov,10 Alvils Krams,11 Branislava Milenkovic,12 Attila Somfay,13 Ruzena Tkacova,14 Neven Tudoric,15 Ruxandra Ulmeanu,16 Arschang Valipour17 1Emek Medical Center, Clalit Healthcare Services, Afula, Israel; 2Department of Pulmonary Medicine, University of Tartu, 3Lung Clinic, Tartu University Hospital, Tartu, Estonia; 4Department of Pulmonology, Russian National Research Medical University, Moscow, Russia; 5Lung Pathophysiology Department, National TB and Lung Diseases Research Institute, Warsaw, Poland; 6Clinic of Infectious Chest Diseases, Dermatovenereology, and Allergology, Vilnius University, Centre of Pulmonology and Allergology, Vilnius University Hospital, Vilnius, Lithuania; 7University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; 8Department of Pneumology, University Hospital, Hradec Králové, Czech Republic; 9Institute of Pulmonary Medicine, Hadassah Medical Center, Jerusalem, Israel; 10Clinic of Pulmonary Diseases, Military Medical Academy, Sofia, Bulgaria; 11Medical Faculty of Latvian University, Riga East University Hospital, Riga, Latvia; 12Clinic for Pulmonary Diseases, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 13Department of Pulmonology, University of Szeged, Deszk, Hungary; 14Department of Respiratory Medicine and Tuberculosis, Faculty of Medicine, PJ Safarik University, Košice, Slovakia; 15School of Medicine, Dubrava University Hospital, Zagreb, Croatia; 16Marius Nasta Institute of Pneumology, Bucharest, Romania; 17Department of Respiratory and Critical Care Medicine, Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Vienna, Austria Abstract: COPD is a complex, heterogeneous condition. Even in the early clinical stages, COPD carries a significant burden, with breathlessness frequently leading to a reduction in exercise capacity and changes that correlate with long-term patient outcomes and mortality. Implementation of an effective management strategy is required to reduce symptoms, preserve lung function, quality of life, and exercise capacity, and prevent exacerbations. However, current clinical practice frequently differs from published guidelines on the management of COPD. This review focuses on the current scientific evidence and expert opinion on the management of moderate COPD: the symptoms arising from moderate airflow obstruction and the burden these symptoms impose, how physical activity can improve disease outcomes, the benefits of dual bronchodilation in COPD, and the limited evidence for the benefits of inhaled corticosteroids in this disease. We emphasize the importance of maximizing bronchodilation in COPD with inhaled dual-bronchodilator treatment, enhancing patient-related outcomes, and enabling the withdrawal of inhaled corticosteroids in COPD in well-defined patient groups. Keywords: dual bronchodilation, inhaled corticosteroid, LAMA, LABA, tiotropium, anticholinergic

Zuzana Zbozinkova,1 Adam Barczyk,2 Ruzena Tkacova,3 Arschang Valipour,4 Neven Tudoric,5 Kirill Zykov,6 Attila Somfay,7 Marc Miravitlles,8 Vladimir Koblizek91Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 2Department of Pneumology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland; 3Department of Respiratory Medicine, Faculty of Medicine, P.J. Safarik University, Kosice, Slovakia; 4Department of Respiratory and Critical Care Medicine, Ludwig-Boltzmann-Institute for COPD and Respiratory Epidemiology, Otto-Wagner-Spital, Wien, Austria; 5School of Medicine Zagreb, University Hospital Dubrava, Zagreb, Croatia; 6Laboratory of Pulmonology, Moscow State University of Medicine and Dentistry named after A.I. Evdokimov, Moscow, Russia; 7Department of Pulmonology, University of Szeged, Deszk, Hungary; 8Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 9Department of Pneumology, Faculty of Medicine in Hradec Kralove, University Hospital Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech RepublicIntroduction: Chronic obstructive pulmonary disease (COPD) constitutes a major health challenge in Central and Eastern European (CEE) countries. However, clinical phenotypes, symptom load, and treatment habits of patients with COPD in CEE countries remain largely unknown. This paper provides a rationale for phenotyping COPD and describes the methodology of a large study in CEE.Methods/design: The POPE study is an international, multicenter, observational cross-sectional survey of patients with COPD in CEE. Participation in the study is offered to all consecutive outpatients with stable COPD in 84 centers across the CEE region if they fulfill the following criteria: age >40 years, smoking history ≥10 pack-years, a confirmed diagnosis of COPD with postbronchodilator FEV1/FVC ,0.7, and absence of COPD exacerbation ≥4 weeks. Medical history, risk factors for COPD, comorbidities, lung function parameters, symptoms, and pharmaceutical and nonpharmaceutical treatment are recorded. The POPE project is registered in ClinicalTrials.gov with the identifier NCT02119494.Outcomes: The primary aim of the POPE study was to phenotype patients with COPD in a real-life setting within CEE countries using predefined classifications. Secondary aims of the study included analysis of differences in symptoms, and diagnostic and therapeutic behavior in participating CEE countries.Conclusion: There is increasing acceptance toward a phenotype-driven therapeutic approach in COPD. The POPE study may contribute to reveal important information regarding phenotypes and therapy in real-life CEE.Keywords: COPD, phenotypes, Central Europe, Eastern Europe, study, GOLD, comorbidity

Aims: Arterial hypertension is highly prevalent and difficult to control in patients with obstructive sleep apnea (OSA). High sympathoadrenergic activity is a hallmark physiological phenomenon in OSA. We hypothesized that an antihypertensive drug with inhibitory properties on this activity, such as beta blockers (BBs), may be particularly efficacious in OSA patients., Methods: Hypertensive OSA patients receiving blood pressure-lowing treatment in the European Sleep Apnea Database (ESADA) (n = 5818, 69% men, age 58 ± 11 years, body mass index 33 ± 7 kg/m2, apnea hypopnea index 34 ± 26 events/h) were analyzed. Reported medications [BB, diuretic, renin-angiotensin blocker (RAB), calcium channel blocker (CCB), and centrally acting antihypertensive (CAH)] were classified according to ATC code. Office blood pressure was compared in patients with monotherapy or combination therapy controlling for confounders., Results: Poorly controlled SBP according to the ESC/ESH guidelines was found in 66% of patients. Patients receiving monotherapy with RAB, CCB or CAH had 2.2 (95% CI 1.4-3.0), 3.0 (1.9-4.1) and 3.0 (1.7-4.7) mmHg higher SBP compared with those on BB (adjusted model, P = 0.007, 0.008 and 0.017, respectively). In those with a combination of two antihypertensive drugs, SBP was 5.5 (4.0-7.1), 5.1 (3.7-6.6), 4.3 (2.5-6.1) and 3.1 (1.6-4.6) mmHg higher in those on CCB/RAB, BB/RAB, BB/CCB or diuretic/RAB compared with those on BB/diuretic (adjusted model, P < 0.001, <0.001, 0.018 and 0.036, respectively)., Conclusion: Poorly controlled blood pressure was common in OSA patients with antihypertensive medication. Treatment with BB alone or BB in combination with a diuretic was associated with the lowest systolic pressure in this large clinical cohort., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To assess the effects of single nucleotide polymorphisms (SNPs) on blood pressure control in patients with obstructive sleep apnea (OSA)., Methods: This prospective observational cohort study, conducted between 2004 and 2014, examined the associations of SNPs of JAG1, GUCY1A3-GUCY1B3, SH2B3, and NPR3-C5orf23 genes with systolic and diastolic blood pressure (SBP, DBP) in 1179 adults evaluated for OSA with overnight polysomnography. Genotyping was performed by unlabeled probe melting analysis., Results: The patients were predominantly male (69.6%, mean age 52±11 years, apnea-hypopnea index 34±31 episodes/h). Only JAG1 genotype was associated with SBP and DBP: compared with AA homozygotes, G allele carriers (pooled GG and AG genotype) had significantly higher morning SBP (132±19 vs 129±18 mm Hg; P=0.009) and morning and evening DBP (85±11 vs 83±10 mm Hg, P=0.004; 86±10 vs 84±10 mm Hg, P=0.012, respectively); the differences remained significant after the correction for multiple SNPs testing. In multivariate analyses, oxygen desaturation index and JAG1 genotype independently predicted morning SBP (P=0.001, P=0.003, respectively) and DBP (P<0.001, P=0.005, respectively), and evening SBP (P=0.019, P=0.048, respectively) and DBP (P=0.018, P=0.018, respectively)., Conclusion: This is the first replication study of the SNPs recently linked to arterial hypertension in general population by genome-wide association studies. Our findings suggest that JAG1 genotype is related to blood pressure control in OSA: G allele was associated with higher morning and evening SBP and DBP.

Understanding apoptosis regulatory mechanisms in endothelial cells (ECs) has great importance for the development of novel therapy strategies for cancer and cardiovascular pathologies. An oxidative stress with the generation of reactive oxygen species (ROS) is a common mechanism causing ECs' dysfunction and apoptosis. The generation of ROS can be triggered by various stimuli including photodynamic therapy (PDT). In most PDT treatments, photosensitizer (PS) is administered systemically, and thus, possibility of high exposure to PS in the ECs remains high. PS accumulation in ECs may be clinically relevant even without PDT, if PS molecules affect the pro-apoptotic cascade without illumination. In the present work, we focused on Hypericin (Hyp) and HypPDT effects on the cell viability, oxidative stress, and the distribution of Bcl2 family members in human coronary artery endothelial (HCAEC) cells. Our findings show that the presence of Hyp itself has an effect on cell viability, oxidative stress, and the distribution of Bcl2 family members, without affecting the mitochondria function. In contrast, HypPDT resulted in mitochondria dysfunction, further increase of oxidative stress and effect on the distribution of Bcl2 family members, and in primarily necrotic type of death in HCAEC cells.