TY - THES A1 - Hartmann, Tanja T1 - Eine detaillierte elektrokardiographische Analyse bei Patienten mit Morbus Fabry und deren klinische Deutung T1 - A detailed electrocardiographic analysis and clinical implications for patients with Fabry disease N2 - Bei Morbus Fabry handelt es sich um eine X-chromosomal rezessiv vererbbare lysosomale Speichererkrankung. Im Vordergrund der kardialen Beteiligung stehen eine progrediente Herzinsuffizienz, bedingt durch eine linksventrikuläre Hypertrophie mit kardialer Fibrosierung, sowie eine Mitbeteiligung des Reizleitungssystems. Bei 150 Patienten wurden im Zeitraum von 2001-2009 neben einer klinischen Untersuchung ein EKG, eine Echokardiographie, ein Belastungs-EKG und teilweise auch eine Magnetresonanztomographie durchgeführt. Zum Vergleich der Patientenentwicklung wurde jeweils das jüngste Follow-up Ergebnis mit den Baseline-Daten verglichen. Es konnte eine signifikante Korrelation zwischen der QRS-Dauer und der Wandstärke in der Echokardiographie und der Magnetresonanztomographie eindeutig nachgewiesen werden. Eine myokardiale Fibrose ist bei normalen Ruhe-EKG-Parametern nahezu auszuschließen. In der Untersuchung des Langzeit-EKGs fanden sich bei einigen Patienten höhergradige ventrikuläre Rhythmusstörungen, welche als erhöhtes individuelles Risiko und als bedeutender Faktor der Sterblichkeit bei Morbus Fabry zu werten sind. N2 - The X-linked recessive genetic disorder Fabry disease is a lysosomal storage disease. Patients present predominantly cardiac involvement e.g. left ventricular hypertrophy and myocardial fibrosis, as well as repolarization abnormalities. In this study, 150 patients underwent physical examinations, EKG studies, echocardiography exams, stress-tests and cardiac MRI studies between 2001 and 2009. Baseline and follow-up results were compared accordingly. The study demonstrated a significant correlation between QRS-Duration and left ventricular wall thickness assessed by echocardiography and cMRI studies. The results showed that an unremarkable EKG study was associated with low probability of myocardial fibrosis. Data from EKG-Holter-monitor-studies demonstrated clinically relevant ventricular arrhythmias in several patients. This indicates an increased individual risk and may determine mortality associated with Fabry disease. KW - Fabry-Krankheit KW - Elektrokardiogramm KW - Transthorakale Echokardiographie KW - Langzeit-Elektrokardiogramm KW - Belastungselektrokardiogramm KW - Morbus Fabry KW - Enzymersatztherapie KW - Fabry disease KW - electrocardiogram KW - enzyme replacement therapy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165610 ER - TY - JOUR A1 - Kirschmer, Nadine A1 - Bandleon, Sandra A1 - von Ehrlich-Treuenstätt, Viktor A1 - Hartmann, Sonja A1 - Schaaf, Alice A1 - Lamprecht, Anna-Karina A1 - Miranda-Laferte, Erick A1 - Langsenlehner, Tanja A1 - Ritter, Oliver A1 - Eder, Petra T1 - TRPC4α and TRPC4β Similarly Affect Neonatal Cardiomyocyte Survival during Chronic GPCR Stimulation JF - PLoS ONE N2 - The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca\(^{2+}\) component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na\(^{+}\) and Ca\(^{2+}\) influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca\(^{2+}\) influx which has been regarded as ideal Ca\(^{2+}\) source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation. Functional properties of TRPC4 are also based on the expression of the TRPC4 splice variants TRPC4α and TRPC4β. Aim of the present study was to analyze cytosolic Ca\(^{2+}\) signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4α or TRPC4β. The analysis of Ca\(^{2+}\) transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4α and TRPC4β affected Ca\(^{2+}\) cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca\(^{2+}\) transient amplitude at baseline and TRPC4β increasing the Ca\(^{2+}\) peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4β (Ad-C4β) also responded with a sustained Ca\(^{2+}\) influx when treated with Ang II under non-pacing conditions. Consistent with the Ca\(^{2+}\) data, NRCs infected with TRPC4α (Ad-C4α) showed an elevated calcineurin/NFAT activity and a baseline hypertrophic phenotype but did not further develop hypertrophy during chronic Ang II/phenylephrine stimulation. Down-regulation of endogenous TRPC4α reversed these effects, resulting in less hypertrophy of NRCs at baseline but a markedly increased hypertrophic enlargement after chronic agonist stimulation. Ad-C4β NRCs did not exhibit baseline calcineurin/NFAT activity or hypertrophy but responded with an increased calcineurin/NFAT activity after GPCR stimulation. However, this effect was not translated into an increased propensity towards hypertrophy but rather less hypertrophy during GPCR stimulation. Further analyses revealed that, although hypertrophy was preserved in Ad-C4α NRCs and even attenuated in Ad-C4β NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4α and TRPC4β differentially affect Ca\(^{2+}\) signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation. KW - Apoptosis KW - calcineurin signaling cascade KW - small interfering RNAs KW - G protein coupled receptors KW - hyperexpression techniques KW - heart KW - adenoviruses KW - cardiac pacing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178539 VL - 11 IS - 12 ER - TY - JOUR A1 - Löb, Sanja A1 - Linsmeier, Eva A1 - Herbert, Saskia-Laureen A1 - Schlaiß, Tanja A1 - Kiesel, Matthias A1 - Wischhusen, Jörg A1 - Salmen, Jessica A1 - Kranke, Peter A1 - Quenzer, Anne A1 - Kurz, Florian A1 - Weiss, Claire A1 - Gerhard-Hartmann, Elena A1 - Wöckel, Achim A1 - Diessner, Joachim T1 - Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important. KW - breast cancer KW - HER2 conversion KW - HER2-low KW - trastuzumab deruxtecan KW - HER2 targeted therapy KW - trastuzumab Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324068 VL - 149 IS - 8 ER -