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Stefan Andreas,1,2 Ulrich Bothner,3 Alberto de la Hoz,3 Isabel Kloer,3 Matthias Trampisch,3 Peter Alter4 1Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Stefan Andreas Department of Cardiology and PneumologyUniversity Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673-501-1101Email stefan.andreas@med.uni-goettingen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing cardiac arrhythmias and elevated heart rate. A theoretical mechanistic association based on the interaction of long-acting β2-agonists (LABAs) with adrenoreceptors in the heart and vasculature is assumed as a potential class-related risk. Therefore, we performed a pooled analysis of Holter electrocardiogram (ECG) data from four 48-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III clinical trials evaluating olodaterol (5 μg or 10 μg) or formoterol (12 μg) versus placebo.Methods: We analyzed Holter ECG data from a representative subset of 775 patients with Global Initiative for Chronic Obstructive Lung Disease stage 2– 4 COPD from four studies (1222.11– 14) assessing olodaterol (5 μg and 10 μg) and formoterol (12 μg) versus placebo.Results: No statistically significant (P> 0.3) or clinically relevant differences in the shift from baseline of premature supraventricular or ventricular beats were observed among the active treatment and the placebo groups. Minor and transient differences were observed in the adjusted mean heart rate from baseline during treatment in all groups. There was a numerically small but statistically significant increase for formoterol at Week 24, olodaterol 5 μg at Weeks 12 and 40, and olodaterol 10 μg at Week 40 (all less than 3.0 beats per minute). Mean heart rates returned to a statistically non-significant change at Week 48 for all treatment groups. No increase in major adverse cardiovascular events was observed.Conclusion: Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD.Trial Registration: ClinicalTrials.gov identifiers: NCT00782210 (1222.11); NCT00782509 (1222.12); NCT00793624 (1222.13); NCT00796653 (1222.14).Keywords: olodaterol, formoterol, arrhythmia, Holter ECG, heart rate

Antonio Klasan,1 Philipp Dworschak,1 Thomas Jan Heyse,1 Steffen Ruchholtz,1 Peter Alter,2 Claus Franz Vogelmeier,2 Patrick Schwarz2 1Department of Orthopedics and Traumatology, University Hospital Marburg, Marburg, Germany; 2Department of Pulmonary and Critical Care Medicine, University Hospital Marburg, Marburg, Germany Purpose: A relevant proportion of patients undergoing joint replacement surgery for the treatment of osteoarthritis exhibit COPD. This coincidence may result from an increased prevalence of both the diseases in elderly patients. In this study, COPD, which is known to be associated with a variety of comorbidities, and its potential interactions, eg, mediated via systemic inflammation, are discussed. The purpose of the present study was to identify the role of COPD as an independent risk factor for complications after total knee and hip arthroplasty.Patients and methods: In a monocentric patient cohort of 2,760 arthoplasties, propensity score matching was done using the following factors: sex, age, replaced joint, American Society of Anesthesiologists’ score, body mass index, hypertension, chronic heart disease, anticoagulation, diabetes mellitus, chronic renal deficiency, and actual smoking status to create 224 pairs. Both the pre-matched differences and the results after propensity score matching were statistically analyzed with p≤0.05 being defined as statistically significant.Results: All confounders were eliminated after matching. Preoperatively measured C-reactive protein and leukocytes were higher in the COPD group (p

Peter Alter,1 Barbara A Mayerhofer,2 Kathrin Kahnert,3 Henrik Watz,4 Benjamin Waschki,5,6 Stefan Andreas,7,8 Frank Biertz,9 Robert Bals,10 Claus F Vogelmeier,1 Rudolf A Jörres2 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the Center for Lung Research (DZL), Munich, Germany; 3Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 5Department of Pneumology, LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 6Department of General and Interventional Cardiology, University Heart Center, Hamburg, Germany; 7Department of Cardiology and Pneumology, University Medical Center, Goettingen, Germany; 8Lung Clinic, Immenhausen, Germany; 9Institute for Biostatistics, Center for Biometry, Medical Informatics and Medical Technology, Hannover Medical School, Hannover, Germany; 10Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, GermanyCorrespondence: Peter AlterDepartment of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Baldingerstrasse 1, Marburg 35033, GermanyTel +49 6 421 586 6140Email Alter@uni-marburg.de&#x00A0Rudolf A JörresInstitute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the Center for Lung Research (DZL), Ziemssenstrasse 1, Munich 80336, GermanyTel +49 8 944 005 2466Email Rudolf.Joerres@med.uni-muenchen.de &#x00A0Background: A substantial prevalence of cardiovascular disease is known for COPD, but detection of its presence, relationship to functional findings and contribution to symptoms remains challenging. The present analysis focusses on the cardiovascular contribution to COPD symptoms and their relationship to the patients’ diagnostic status, medication and echocardiographic findings.Methods: Patients from the COPD cohort COSYCONET with data on lung function, including FEV1, residual volume/total lung capacity (RV/TLC) ratio, diffusing capacity TLCO, and echocardiographic data on left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD), medical history, medication, modified British Medical Research Council dyspnea scale (mMRC) and Saint Georges Respiratory Questionnaire (SGRQ) were analyzed.Results: A total of 1591 patients (GOLD 0–4: n=230/126/614/498/123) fulfilled the inclusion criteria. Ischemic heart disease, myocardial infarction or heart failure were reported in 289 patients (18.2%); 860 patients (54%) received at least one cardiovascular medication, with more than one in many patients. LVEF56 mm was found in 204 patients (12.8%), of whom 74 (36.3%) had neither a cardiovascular history nor medication. Among 948 patients (59.6%) without isolated hypertension, there were 21/55 (38.2%) patients with LVEF56 mm, who lacked both a cardiac diagnosis and medication. LVEDD and LVEF were linked to medical history; LVEDD was dependent on RV/TLC and LVEF on FEV1. Exertional COPD symptoms were best described by mMRC and the SGRQ activity score. Beyond lung function, an independent link from LVEDD on symptoms was revealed.Conclusion: A remarkable proportion of patients with suspicious echocardiographic findings were undiagnosed and untreated, implying an increased risk for an unfavorable prognosis. Cardiac size and function were dependent on lung function and only partially linked to cardiovascular history. Although the contribution of LV size to COPD symptoms was small compared to lung function, it was detectable irrespective of all other influencing factors. However, only the mMRC and SGRQ activity component were found to be suitable for this purpose.Keywords: COPD, heart failure, echocardiography, medication, dyspnea, symptoms

Frits ME Franssen1,2, Peter Alter,3 Nadav Bar,4 Birke J Benedikter5,6, Stella Iurato,7 Dieter Maier,8 Michael Maxheim,3 Fabienne K Roessler,4 Martijn A Spruit,1–2,9 Claus F Vogelmeier,3 Emiel FM Wouters1,2, Bernd Schmeck3,5 On behalf of the SysMed-COPD consortium 1Department of Research and Education, CIRO, Horn, The Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands; 3Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 4Department of Chemical Engineering, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 5Institute for Lung Research, Universities of Giessen and Marburg Lung Centre, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 6Department of Medical Microbiology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands; 7Viscovery Software GmbH, Vienna, Austria; 8Biomax Informatics AG, Planegg, Germany; 9REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, BelgiumAbstract: Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD.Keywords: chronic obstructive pulmonary disease, personalized medicine, systems medicine, review