Genetic Background and Biomarkers of Atrial Fibrillation Progression and Recurrence

Vorhofflimmern (VHF) ist eine progressive Krankheit, die sich morphologisch als fibrotische Remodellierung des Vorhofs manifestiert und klinisch durch einen Wechsel von paroxysmalem zu persistierendem VHF, eine Vergrößerung des links-atrialen Diameters und die intra-prozedurale Detektion von atrialen Bereichen mit niedrigen Potentialen gekennzeichnet ist. VHF-Progression ist mit schlechteren Therapieergebnissen, z.B. einer höheren VHF-Rezidivrate assoziiert. Zugrunde liegende Pathomechanismen sind unvollständig charakterisiert, geeignete Biomarker zur individuellen therapeutischen Stratifizierung sind nicht bekannt. Die Mehrzahl häufiger genetischer Varianten, die mit der VHF-Progression assoziiert sind, hat nur sehr kleine Effekte. Viele Varianten könnten hingegen additiv die Progression von VHF modulieren. Dieser Hypothese folgend wurden mit VHF-Progression assoziierte Varianten identifiziert und deren nicht-zufällige Häufung in Gen-Loci als Indiz für eine kontextuelle Relevanz des jeweiligen Gens gewertet. Die identifizierten Gene wurden der Kalzium-Signaltransduktion und der extrazelluläre Matrix (ECM)-Rezeptor-Interaktion zugeordnet. Zusätzlich wurden die zentralen Regulatoren dieser Signalwege, namentlich EGFR, RYR2, PRKCA, FN1 und LAMA1 identifiziert, die als pharmakologische Ziele in Frage kommen bzw. hinsichtlich ihrer Rolle bei der VHF-Progression untersucht werden müssen. Mit einer vergleichbaren Herangehensweise wurde gezeigt, dass die mit der Manifestation von VHF assoziierten Gene ZFHX3, ITGA9 und SOX5 auch mit der VHF-Progression assoziiert sind. Eine Analyse potentieller Biomarker identifizierte NT-pro ANP als spezifischen Marker mit direkter Korrelation zum Progressionsgrad des VHF. Zusätzlich wurde für die Marker NT-proANP, NT-proBNP und VCAM1 ein stufenweise signifikanter Anstieg korrelierend mit einem klinischen Wert zur Prognose von VHF-Rezidiven gezeigt. Durch die Anwendung unkonventioneller Konzepte und der Verwendung spezifischer Charakteristika der VHF-Progression konnten in der vorliegenden Arbeit potentielle Regulatoren und Biomarker der VHF-Progression identifiziert werden.:1. Introduction 5 1.1. Atrial fibrillation incidence and associated risk 5 1.2. Atrial fibrillation therapy and recurrence 6 1.3. Atrial fibrillation progression phenotypes 7 1.3.1. Atrial fibrillation type 7 1.3.2. Left atrial diameter 8 1.3.3. Low voltage areas 8 1.3.4. PR interval 8 1.4. Pathomechanisms of atrial fibrillation progression 9 1.4.1. Electrical remodeling 9 1.4.2. Structural remodeling and fibrosis 10 1.4.3. Autonomic remodeling 11 1.5. Genetic background of atrial fibrillation 11 1.5.1. Heritable atrial fibrillation and the impact of rare variants 12 1.5.2. Genetic predisposition and the impact of common variants 12 1.5.3. New concepts for GWAS analysis of genetic background 13 1.6. Personalized medicine 15 1.6.1. Clinical scores for risk prediction in atrial fibrillation 15 1.6.2. Clinical scores for prediction of AF progression and recurrence 15 1.6.3. New concepts in personalized medicine 16 1.7.1. Schematic overview on AF progression and associated open questions 16 2. Hypotheses 18 3. Publications 19 3.1. New concepts on genetic background of AF progression and recurrence 19 3.1.1. Genomic contributors to atrial electroanatomical remodeling and atrial fibrillation progression: Pathway enrichment analysis of GWAS data. (Publication 1) 20 3.1.2. Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation - Pathway Enrichment Analysis of GWAS Data. (Publication 2) 28 3.1.3. Identification of Central Regulators of Calcium Signaling and ECM-Receptor Interaction Genetically Associated With the Progression and Recurrence of Atrial Fibrillation. (Publication 3) 40 3.1.4. Association of atrial fibrillation susceptibility genes, atrial fibrillation phenotypes and response to catheter ablation: a gene-based analysis of GWAS data. (Publication 4) 47 3.1.5. PR Interval Associated Genes, Atrial Remodeling and Rhythm Outcome of Catheter Ablation of Atrial Fibrillation—A Gene-Based Analysis of GWAS Data. (Publication 5) 54 3.2. New concepts on biomarkers of AF progression and recurrence 3.2.1. Role of NT-proANP and NT-proBNP in patients with atrial fibrillation: Association with atrial fibrillation progression phenotypes. (Publication 6) 61 3.2.2. Prediction of electro-anatomical substrate using APPLE score and biomarkers. (Publication 7) 68 4. Conclusions 75 5. References 76 6. Abbreviations 86 7. Erklärungen zur vorgelegten Habilitationsschrift 87 8. Lebenslauf 88 9. Danksagung 9

Epidemiology

Epidemiology is a methodological, well grounded and versatile tool-kit to conduct evidence-based quantitative research in all health sciences. It integrates a wide spectrum of case studies and examples from the different disciplines thereby fostering the multi-disciplinary approach in the health sciences. It follows a two level 'methods based' approach differentiating between "basic" knowledge that all students of epidemiology should be familiar with and "beyond the basics" information for the interested or more advanced reader

Epidemiology

Epidemiology 2nd edition is a methodological and practical guide to conducting evidence-based quantitative research in all health sciences. With a multidisciplinary focus, it integrates a wealth of case studies and examples to demonstrate the application of theory to real-life research and draws from a broad spectrum of health disciplines. The book follows a two level 'methods based' approach which clearly differentiates between introductory knowledge that all students of epidemiology should be familiar with and 'beyond the basics' information for the interested or more advanced reader. Each chapter includes tips, key definitions and critical thinking exercises to help readers engage with key concepts and extend their knowledge of epidemiological methodologies

Analyse der Veränderungen der Genexpression weißer Blutzellen des Menschen in Reaktion auf körperliche Belastung

Physische Belastung verursacht vielfältige Reaktionen im menschlichen Organsimus. In dieser Arbeit wurde in drei aufeinander aufbauenden Studien geprüft, ob und wie physische Belastung Veränderungen in den Genexpressionsmustern (GEM) weißer Blutzellen induzieren kann. Es konnte gezeigt werden, dass GEM weißer Blutzellen sensitiv die Intensität akuter Belastung wiederspiegeln. Weiterhin konnten zahlreiche immunzellspezifische und energieliefernde Stoffwechselprozesse identifiziert werden, die in T-Lymphozyten und Monozyten in Reaktion auf langanhaltende intensive Belastung (Hochleistungsradsport) verändert reguliert werden

Effectiveness of Lifestyle Measures in the Treatment of Gastroesophageal Reflux Disease — A Case Series

Aim: To assess the effectiveness of lifestyle measures in the treatment of gastroesophageal reflux disease (GERD) among adults attending a dietetic practice.\ud \ud Methods: A retrospective case series of adult patients presenting with GERD to a dietetic practice over a three year period. The routine lifestyle counselling for treatment of symptoms of GERD included: not reclining within two to three hours of eating; a diet low in fat; small frequent meals; avoiding dietary components considered to relax the lower esophageal sphincter; and avoiding local irritants.\ud \ud Results: Twenty three cases were included (12 male). Eighteen, (9 female) were referred by their doctor, 7 (6 female) presented for GERD alone, 7 (4 female) presented for GERD together with comorbidities, and 9 (1 female) incidentally mentioned GERD during a dietary consultation for another disorder. Thirteen participants (9 female) had previously undergone endoscopies, 18 (11 female) were taking medication for GERD, and 19 (7 female) had comorbidities. Twenty two (10 female) reported an improvement in symptoms with 11/18 taking GERD medication at presentation reducing their medication following treatment.\ud \ud Conclusions: These results suggest that a more thorough investigation of lifestyle modification in the treatment of GERD is warranted

Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD

Automated Detection of Forest Gaps in Spruce Dominated Stands Using Canopy Height Models Derived from Stereo Aerial Imagery

Forest gaps are important structural elements in forest ecology to which various conservation-relevant, photophilic species are associated. To automatically map forest gaps and detect their changes over time, we developed a method based on Digital Surface Models (DSM) derived from stereoscopic aerial imagery and a LiDAR-based Digital Elevation Model (LiDAR DEM). Gaps were detected and delineated in relation to height and cover of the surrounding forest comparing data from two public flight campaigns (2009 and 2012) in a 1023-ha model region in the Northern Black Forest, Southwest Germany. The method was evaluated using an independent validation dataset obtained by visual stereo-interpretation. Gaps were automatically detected with an overall accuracy of 0.90 (2009) and 0.82 (2012). However, a very high producers’ accuracy of more than 0.95 (both years) was counterbalanced by a user’s accuracy of 0.84 (2009) and 0.73 (2012) as some gaps were not automatically detected. Accuracy was mainly dependent on the shadow occurrence and height of the surrounding forest with user’s accuracies dropping to 0.70 (2009) and 0.52 (2012) in high stands (>8 m tree height). As one important step in the workflow, the class of open forest, an important feature for many forest species, was delineated with a very good overall accuracy of 0.92 (both years) with uncertainties occurring mostly in areas with intermediate canopy cover. Presence of complete or partial shadow and geometric limitations of stereo image matching were identified as the main sources of errors in the method performance, suggesting that images with a higher overlap and resolution and ameliorated image-matching algorithms provide the greatest potential for improvement

Risk of dissemination of relevant phytopathogens of potato with agricultural use of sewage sludge

Klärschlamm stellt einen bedeutsamen Sekundärrohstoffdünger dar, der grundsätzlich für eine Verwendung in der Landwirtschaft geeignet ist. Abhängig von der Herkunft des Klärschlammes, kann dieser mit verschiedenen Tier-, Human- und Pflanzenpathogenen belastet sein. Anhand von Literaturangaben erfolgte eine Bewertung verschiedener Klärschlammbehandlungsverfahren hinsichtlich der Wirkung auf relevante Schadorganismen der Kartoffel und das damit verbundene Risiko der Verbreitung solcher Schadorganismen mit Klärschlamm bei landwirtschaftlicher Verwertung. Entsprechend der vorliegenden Literatur muss davon ausgegangen werden, dass eine vollständige Abtötung widerstandsfähiger Schadorganismen durch übliche Klärschlammbehandlungsverfahren nicht gesichert ist. Dies betrifft vor allem eine mögliche Kontamination mit den in der Richtlinie 2000/29/EG gelisteten Schadorganismen der Kartoffel, vor allem mit Synchytrium endobioticum, dem Erreger des Kartoffelkrebses. Um eine Verbreitung solcher Schadorganismen auszuschließen, sollte auf eine Einleitung risikoreicher Abwässer, z.B. aus der Kartoffelverarbeitung, in kommunale Kläranlagen, bzw. eine Verwendung von Klärschlamm in der Landwirtschaft nach Einleitung risikoreicher Abwässer verzichtet werden. DOI: 10.5073/JfK.2014.12.01, https://doi.org/10.5073/JfK.2014.12.01Sewage sludge is a significant fertilizer that is generally suitable for usage in agriculture. Depending on the origin of the sewage sludge, it can be contaminated with various animal, human or plant pathogens. Based on literature data, current sewage sludge treatments were analyzed regarding their effectiveness on the inactivation of relevant pathogens of potatoes and the associated risk of their dissemination when sewage sludge is used in agriculture. According to the available literature it has to be concluded, that treatments usually applied in Germany will not be sufficient for complete inactivation of robust phytopathogens. This refers mainly to pathogens of po­tato that are listed in Directive 2000/29/EC, especially Synchytrium endobioticum, the agent for potato wart disease. Therefore, risky waste waters, e.g. from potato processing industries, should not be introduced in municipal waste waters or sewage sludge produced from such risky waste water should not be used in agriculture, to avoid the possible dissemination of such phytopathogens. DOI: 10.5073/JfK.2014.12.01, https://doi.org/10.5073/JfK.2014.12.0

Everolimus-Induced Immune Effects after Heart Transplantation: A Possible Tool for Clinicians to Monitor Patients at Risk for Transplant Rejection

Background: Patients treated with an inhibitor of the mechanistic target of rapamycin (mTORI) in a calcineurin inhibitor (CNI)-free immunosuppressive regimen after heart transplantation (HTx) show a higher risk for transplant rejection. We developed an immunological monitoring tool that may improve the identification of mTORI-treated patients at risk for rejection. Methods: Circulating dendritic cells (DCs) and regulatory T cells (Tregs) were analysed in 19 mTORI- and 20 CNI-treated HTx patients by flow cytometry. Principal component and cluster analysis were used to identify patients at risk for transplant rejection. Results: The percentages of total Tregs (p = 0.02) and CD39+ Tregs (p = 0.05) were higher in mTORI-treated patients than in CNI-treated patients. The principal component analysis revealed that BDCA1+, BDCA2+ and BDCA4+ DCs as well as total Tregs could distinguish between non-rejecting and rejecting mTORI-treated patients. Most mTORI-treated rejectors showed higher levels of BDCA2+ and BDCA4+ plasmacytoid DCs and lower levels of BDCA1+ myeloid DCs and Tregs than mTORI non-rejectors. Conclusion: An mTORI-based immunosuppressive regimen induced a sufficient, tolerance-promoting reaction in Tregs, but an insufficient, adverse effect in DCs. On the basis of patient-specific immunological profiles, we established a flow cytometry-based monitoring tool that may be helpful in identifying patients at risk for rejection