TY - THES A1 - Brunner, Thomas T1 - Nutzen eines implantierten Event Recorders zur Detektion von klinisch relevanten Rhythmusstörungen bei Patienten mit fortgeschrittener Fabry - Kardiomyopathie T1 - Usefulness of an Implantable Loop Recorder to Detect Clinically Relevant Arrhythmias in Patients With Advanced Fabry Cardiomyopathy N2 - Der Morbus Fabry ist eine X-chromosomal rezessive, lysosomale Speicherkrankheit, die durch eine Mutation im α - Galactosidase A Gen verursacht wird. Dadurch werden unter anderem Bestandteile der Plasmamembran (Globotriaosylceramide) nicht mehr degradiert und sie akkumulieren intrazellulär. Daraus resultiert, vom anfänglichen Einzelzellschäden, letzten Endes ein oftmals schwerer Organschaden mit Funktionsausfällen. Die einzige kausale Therapie besteht in der Substituierung des betroffenen Enzyms. Der Morbus Fabry äußert sich klinisch als eine Multisystemerkrankung mit hauptsächlich renaler, nervaler, sowie kardialer Beteiligung. Vor allem letztere ist maßgeblich für die verkürzte Lebenserwartung verantwortlich. Die Patienten entwickeln mit Progression der Erkrankung häufig eine linksventrikuläre Hypertrophie, eine Herzinsuffizienz und durch die zunehmende Akkumulation der Globotriaosylceramide entsteht im Verlauf ein fibrotischer Umbau im Myokard. Dies ist möglicherweise auch der Entstehungsort für maligne Rhythmusstörungen. Wissenschaftlich erforscht ist, dass supraventikuläre sowie ventrikuläre Tachykardien bzw. Bradykardien bis hin zu Asystolie/Pausen bei diesen Patienten auftreten können. Ebenso weiß man, dass man mit Hilfe von so genannten Event Recordern, die kontinuierlich die elektrische Herzaktivität überwachen und die Daten via Telemetrie an ein Zentrum senden, die Detektionsrate von Rhythmusstörungen erhöhen kann. Aber ob solch ein Event Recorder auch bei Patienten mit fortgeschrittener Fabry - Kardiomyopathie einen Nutzen hat und sie bei diesen Patienten zur Detektion von malignen Rhythmusstörungen beitragen ist bisher unklar und Thema dieser Studie. Insgesamt implantierte man 16 Patienten (12 Männer / 4 Frauen), mit einem gesicherten Morbus Fabry, einen Event Recorder. Sie erhielten 7,4 ± 4,5 Jahren die Enzymersatztherapie, wurden über einen Zeitraum von 0,3 - 2 Jahren beobachtet und übertrugen ihre Daten durchschnittlich 14 ± 11 mal pro Monat. Dabei konnten insgesamt 8547 klinisch relevante Übertragungen aufgezeichnet werden, die entsprechend der Studieneinteilung in Asystolie, Bradykardie, Vorhofflimmern, und ventrikuläre Tachykardie eingeteilt worden sind. Asystolie Episoden, mit elektrischen Pausen von 3,3 bis 4,4 Sekunden, wurden insgesamt 66-mal bei 4 Patienten mit dem Event Recorder aufgezeichnet. Über 8000 Bradykardien konnten bei 6 Männern und 1 Frau dokumentiert werden, darunter ein AV-Block II° Typ Mobitz mit ei ner 2:1 Überleitung. Fast 370-mal konnte ein intermittierendes Vorhofflimmern bzw. Vorhofflattern, mit Flimmerzeiten von 10 Sekunden bis maximal 86400 Sekunden, dargestellt werden. Bei insgesamt 5 Patienten konnten 10 ventrikuläre Tachykardie – Episoden, mit einer maximalen Herzfrequenz 206 Schlägen / min, durch den Event Recorder aufgezeichnet werden. So konnten selbst bei dieser kleinen Kohorte, mit dem Event Recorder, viele klinisch relevante Herzrhythmusstörungen detektiert werden. Auf Grundlage dieser Daten sprach man im Verlauf bei den entsprechenden Patienten eine Empfehlung zur Therapieänderungen aus um klinische Komplikationen zu verhindern. Dies führte letzten Endes zu der Schlussfolgerung, dass der Einsatz von Event Recordern sicherlich ein sehr nützliches diagnostisches Instrument zur Detektion von malignen Rhythmusstörungen bei Patienten mit einer fortgeschrittenen Fabry-Kardiomyopathie ist. Es sollte nun weiter geprüft werden, ob der Event Recorder bereits in früheren Stadien des Morbus Fabry zum Einsatz kommen sollte. N2 - Patients with fabry cardiomyopathy often develop clinically relevant arrhythmias that increase the risk of sudden death. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holter electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in “loco typico.” No patients previously exhibited clinically relevant arrhythmias on Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 – 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses ‡3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverteredefibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder. KW - Fabry Kardiomyopathie KW - Fabry Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-155528 ER - TY - JOUR A1 - Mueller, Kerstin A1 - Quandt, Jasmin A1 - Marienfeld, Ralf B. A1 - Weihrich, Petra A1 - Fiedler, Katja A1 - Claussnitzer, Melina A1 - Laumen, Helmut A1 - Vaeth, Martin A1 - Berberich-Siebelt, Frederike A1 - Serfling, Edgar A1 - Wirth, Thomas A1 - Brunner, Cornelia T1 - Octamer-dependent transcription in T cells is mediated by NFAT and \(NF-\kappa B\) JF - Nucleic Acids Research N2 - The transcriptional co-activator BOB.1/OBF.1 was originally identified in B cells and is constitutively expressed throughout B cell development. BOB.1/OBF.1 associates with the transcription factors Oct1 and Oct2, thereby enhancing octamer-dependent transcription. In contrast, in T cells, BOB.1/OBF.1 expression is inducible by treatment of cells with PMA/Ionomycin or by antigen receptor engagement, indicating a marked difference in the regulation of BOB.1/OBF.1 expression in B versus T cells. The molecular mechanisms underlying the differential expression of BOB.1/OBF.1 in T and B cells remain largely unknown. Therefore, the present study focuses on mechanisms controlling the transcriptional regulation of BOB.1/OBF.1 and Oct2 in T cells. We show that both calcineurin- and \(NF-\kappa B\)-inhibitors efficiently attenuate the expression of BOB.1/OBF.1 and Oct2 in T cells. In silico analyses of the BOB.1/OBF.1 promoter revealed the presence of previously unappreciated combined NFAT/\(NF-\kappa B\) sites. An array of genetic and biochemical analyses illustrates the involvement of the \(Ca^{2+}\)/calmodulin-dependent phosphatase calcineurin as well as NFAT and \(NF-\kappa B\) transcription factors in the transcriptional regulation of octamer-dependent transcription in T cells. Conclusively, impaired expression of BOB.1/OBF.1 and Oct2 and therefore a hampered octamer-dependent transcription may participate in T cell-mediated immunodeficiency caused by the deletion of NFAT or \(NF-\kappa B\) transcription factors. KW - germinal center formation KW - OBF-1 OCA-B KW - coactivator OBF-1 KW - gene expression KW - functional characterization KW - immunoglobulin promoters KW - OCT-1-deficient mice KW - embryonic lethality KW - endothelial cells KW - murine homolog Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123280 SN - 1362-4962 VL - 41 IS - 4 ER - TY - JOUR A1 - Lang, Stefan J. A1 - Messmer, Elisabeth M. A1 - Geerling, Gerd A1 - Mackert, Marc J. A1 - Brunner, Tobias A1 - Dollak, Sylvia A1 - Kutchoukov, Borislav A1 - Böhringer, Daniel A1 - Reinhard, Thomas A1 - Maier, Philip T1 - Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus JF - BMC Ophthalmology N2 - Background: Corneal cross-linking is widely used to treat keratoconus. However, to date, only limited data from randomized trials support its efficacy. Methods: The efficacy and safety of corneal cross-linking for halting progression of keratoconus were investigated in a prospective, randomized, blinded, placebo controlled, multicentre trial. Twenty-nine keratoconus patients were randomized in three trial centres. The mean age at inclusion was 28 years. Longitudinal changes in corneal refraction were assessed by linear regression. The best corrected visual acuity, surface defects and corneal inflammation were also assessed. These data were analysed with a multifactorial linear regression model. Results: A total of 15 eyes were randomized to the treatment and 14 to the control group. Follow-up averaged 1098 days. Corneal refractive power decreased on average (+/-standard deviation) by 0.35 +/- 0.58 dioptres/year in the treatment group. The controls showed an increase of 0.11 +/- 0.61 dioptres/year. This difference was statistically significant (p = 0.02). Conclusions: Our data suggest that corneal cross-linking is an effective treatment for some patients to halt the progression of keratoconus. However, some of the treated patients still progressed, whereas some untreated controls improved. Therefore, further investigations are necessary to decide which patients require treatment and which do not. KW - ultraviolet-a KW - riboflavin KW - Scheimpflug KW - eyes KW - haze Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151498 VL - 15 IS - 78 ER - TY - JOUR A1 - Ruf, Katharina A1 - Thomas, Wolfgang A1 - Brunner, Maximilian A1 - Speer, Christian P. A1 - Hebestreit, Helge T1 - Diverging effects of premature birth and bronchopulmonary dysplasia on exercise capacity and physical activity – a case control study JF - Respiratory Research N2 - Background Extreme prematurity has been associated with exercise intolerance and reduced physical activity. We hypothesized that children with bronchopulmonary dysplasia (BPD) would be especially affected based on long-term lung function impairments. Therefore, the objective of this study was to compare exercise capacity and habitual physical activity between children born very and extremely preterm with and without BPD and term-born children. Methods Twenty-two school-aged children (aged 8 to 12 years) born with a gestational age < 32 weeks and a birthweight < 1500 g (9 with moderate or severe BPD (=BPD), 13 without BPD (=No-BPD)) and 15 healthy term-born children (=CONTROL) were included in the study. Physical activity was measured by accelerometry, lung function by spirometry and exercise capacity by an incremental cardiopulmonary exercise test. Results Peak oxygen uptake was reduced in the BPD-group (83 ± 11%predicted) compared to the No-BPD group (91 ± 8%predicted) and the CONTROL group (94 ± 9%predicted). In a general linear model, variance of peak oxygen uptake was significantly explained by BPD status and height but not by prematurity (p < 0.001). Compared to CONTROL, all children born preterm spent significantly more time in sedentary behaviour (BPD 478 ± 50 min, No-BPD 450 ± 52 min, CONTROL 398 ± 56 min, p < 0.05) and less time in moderate-to-vigorous-physical activity (BPD 13 ± 8 min, No-BPD 16 ± 8 min, CONTROL 33 ± 16 min, p < 0.001). Prematurity but not BPD contributed significantly to explained variance in a general linear model of sedentary behaviour and likewise moderate-to-vigorous-physical activity (p < 0.05 and p < 0.001 respectively). Conclusion In our cohort, BPD but not prematurity was associated with a reduced exercise capacity at school-age. However, prematurity regardless of BPD was related to less engagement in physical activity and more time spent in sedentary behaviour. Thus, our findings suggest diverging effects of prematurity and BPD on exercise capacity and physical activity." KW - Bronchopulmonary dysplasia KW - Physical activity KW - Exercise testing KW - Preterm birth KW - Exercise capacity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202449 VL - 20 ER - TY - JOUR A1 - Weidemann, Frank A1 - Maier, Sebastian K. G. A1 - Störk, Stefan A1 - Brunner, Thomas A1 - Liu, Dan A1 - Hu, Kai A1 - Seydelmann, Nora A1 - Schneider, Andreas A1 - Becher, Jan A1 - Canan-Kühl, Sima A1 - Blaschke, Daniela A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Usefulness of an implantable loop recorder to detect clinically relevant arrhythmias in patients with advanced fabry cardiomyopathy JF - The American Journal of Cardiology N2 - Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder. KW - Cardiovascular magnetic-resonance KW - Coronary artery disease KW - Ventricular-arrhythmias KW - Task force KW - Management KW - Enzyme replacement therapy KW - Hypertrophic cardiomyopathy KW - Myocardial fibrosis KW - Guidelines KW - Manifestation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188093 VL - 118 IS - 2 ER -