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Die Wirkung von Baicalein und Zileuton auf das Knochengewebe am ovarektomierten Rattenmodell
No full textDie Osteoporose, als weltweit häufigste metabolische Knochenerkrankung, rückt nicht nur auf Grund einer zunehmend alternden Bevölkerung in den Fokus der Forschung. Diese Erkrankung hat auch weitreichende Folgen für Betroffene sowie für die Gesellschaft und das Gesundheitssystem. Die häufigste Form ist die postmenopausale Osteoporose, welche eine der häufigsten Knochenerkrankungen der Industrieländer ist. Hervorgerufen durch den postmenopausalen Östrogenabfall, ist diese Erkrankung durch eine verminderte Knochendichte charakterisiert und führt zu einer verminderten Festigkeit der Knochen mit erhöhtem Frakturrisiko.
Lipoxygenasen sind eine Familie von Enzymen, die über ihre Produkte an Entzündungsvorgängen im Körper beteiligt sind, so zum Beispiel bei entzündlichen Erkrankungen wie Asthma oder Psoriasis. Zudem sind Lipoxygenasen über Interleukine und den Tumor-Nekrose-Faktor-⍺ an der Pathogenese der Osteoporose beteiligt. Das Flavonoid Baicalein ist ein Inhibitor der Lipoxygenasen 12 und 15. Nachdem dieses Präparat schon lange in der traditionellen chinesischen Medizin eingesetzt wurde, bestätigen neuere Studien eine positive Wirkung in der Behandlung von Krankheiten mit chronischer Entzündung. Zileuton ist ein Benzothiophen N-Hydroxyharnstoff und inhibiert die Lipoxygenase 5, welche an der Synthese von Leukotrienen beteiligt ist. Auf Grund der Reduktion der Leukotriene durch die Inhibierung der Lipoxygenase 5 wird Zileuton in der Therapie von Asthma eingesetzt. In mehreren Studien zu diesen beiden Präparaten zur Behandlung der Osteoporose, sowohl in vitro als auch in vivo, zeigten sich positive Eigenschaften der beiden Lipoxygenaseinhibitoren Baicalein und Zileuton auf das Knochengewebe.
Ziel dieser Studie war es zu erforschen, ob eine prophylaktische Behandlung sowie eine kombinierte Anwendung von Baicalein und Zileuton weitere Vorteile für den Knochen bringen. Für diese Untersuchung wurde das ovarektomierte Rattenmodel gewählt, das bereits in der Forschung zur postmenopausalen Osteoporose etabliert ist. Dies ist darauf zurückzuführen, dass die Charakteristika des Knochenschwundes ähnlich zu denen beim Menschen sind. Das Femur und der Lendenwirbelkörper wurden für die Versuche gewählt, da diese beiden Knochen sehr häufig von osteoporotischen Frakturen betroffen sind.
Für den Versuch wurden 70 weibliche Sprague Dawley Ratten randomisiert in fünf Gruppen eingeteilt. Im Alter von 12 Wochen wurden 56 Tiere ovarektomiert, um den Zustand einer postmenopausalen Osteoporose hervorzurufen. Von den ovarektomierten Tieren wurde eine Gruppe mit Baicalein, eine mit Zileuton und eine mit einer Kombination aus beiden in einer Dosierung von 10 mg/kg KG über das Futter behandelt. Eine ovarektomierte Gruppe wurde nicht therapiert und diente als ovarektomierte Kontrollgruppe. Eine weitere Kontrollgruppe bestand aus den nicht-ovarektomierten gesunden Tieren. 13 Wochen nach der Ovarektomie wurden Serum, Femora und Lendenwirbelkörper für weitere Untersuchungen entnommen. Zur Untersuchung der Knochenstruktur wurden in einer Mikro-Computertomographie 2D- und 3D-Bilder erstellt und analysiert. In einem Kompressionstest an den Lendenwirbelkörpern und einem Drei-Punkte-Bruchtest an den Femora wurden die biomechanischen Eigenschaften wie die Stabilität und die Elastizität der Knochen gemessen. Nach Veraschung der Knochen wurden die organischen und anorganischen Knochenanteile sowie der Phosphat-, Kalzium- und Magnesiumanteil bestimmt. Des Weiteren erfolgte die Bestimmung von alkalischer Phosphatase, Osteocalcin, RatLaps, Kalzium, Magnesium und Phosphor im Serum. Die statistischen Unterschiede wurden mittels one way analysis of variance (p < 0,05) sowie durch den Tukey-Kramer-post-hoc-Test (p < 0,05) bestimmt.
Die Ergebnisse unserer Studie belegen, dass eine Ovarektomie bei Ratten zu Veränderungen verschiedener Knochenparameter führt. Dabei wurde eine Zunahme des Körpergewichts, der Futteraufnahme und der alkalischen Phosphatase im Serum beobachtet, während das Uterusgewicht und die meisten Knochenparameter abnahmen. Diese Veränderungen entsprechen den zu erwartenden Auswirkungen einer Ovarektomie auf die Knocheneigenschaften von Ratten.
Die zuvor berichteten positiven Effekte von Baicalein und Zileuton konnten durch einen längeren Behandlungszeitraum und durch eine prophylaktische Applikation in dieser Studie nicht bestätigt werden. Die Behandlung mit Baicalein führte lediglich zu einer geringfügigen Veränderung der Knochenparameter, wobei eine Reduktion des Knochen- und Trabekelvolumens zu beobachten war. Der Effekt von Zileuton war ebenfalls von geringer Intensität, was sich in einer Erhöhung des Kalzium-Phosphat-Verhältnisses im Knochen manifestierte. Die Kombination der beiden Substanzen Baicalein und Zileuton resultierte in einer Reduktion des Knochen- und Kortikalisvolumens, der Kortikalisdichte sowie des Kalzium-Phosphat-Verhältnisses. Die Mehrzahl der Knochen- und Serumparameter wies im Vergleich zur unbehandelten OVX-Gruppe keine Veränderung auf. Die mittels 2D-Mikro-CT-Analyse gewonnenen Daten wichen von den mittels 3D-Analyse ermittelten Daten ab. Aufgrund der Betrachtung des gesamten Knochens im Rahmen in der 3D-Analyse wurde bei der Dateninterpretation der Fokus auf diese Ergebnisse gelegt.
Ein Einfluss der Lipoxygenaseinhibitoren auf das Körpergewicht, die Futteraufnahme und die Uterusgewichte der Tiere wurde nicht beobachtet. Ebenso zeigte sich keine Wirkung auf die biomechanischen Knocheneigenschaften.
Zusammenfassend lässt sich feststellen, dass eine prophylaktische orale Applikation der Lipoxygenaseinhibitoren Baicalein und Zileuton und einer Kombination aus beiden nur geringe Auswirkungen auf das Knochengewebe des Femurs und des Lendenwirbelkörpers der ovarektomierten Ratte hat. Zudem zeigten sich vor allem durch die Kombination negative Effekte auf das Knochengewebe, sodass diese Lipoxygenaseinhibitoren nicht als prophylaktische Therapie der Osteoporose empfohlen werden können. In zukünftigen Studien könnte die Anwendung von Lipoxygenaseinhibitoren in Bezug auf die chronische Entzündung bzw. die Entzündungsmarker im Rahmen einer postmenopausalen Osteoporose untersucht werden und dadurch der optimale Zeitpunkt für deren Einsatz bestimmt werden.Osteoporosis is the most common metabolic bone disease worldwide and has gained increasing attention in research, not only due to a progressively aging population but also because of its broad impact on patients, society, and healthcare systems. The most prevalent form, postmenopausal osteoporosis, represents one of the most frequent bone disorders in industrialized countries. Triggered by the postmenopausal decline in estrogen, the condition is characterized by reduced bone density, leading to impaired bone strength and an elevated risk of fractures.
Lipoxygenases constitute a family of enzymes that participate in inflammatory processes and are implicated in disorders such as asthma and psoriasis. Moreover, they are involved in the pathogenesis of osteoporosis through interleukin- and tumor necrosis factor-α-mediated mechanisms. Baicalein, a flavonoid that inhibits lipoxygenases 12 and 15, has long been used in Traditional Chinese Medicine and has more recently been shown to exert beneficial effects in chronic inflammatory diseases. Zileuton, a benzothiophene N-hydroxyurea derivative, inhibits 5-lipoxygenase, an enzyme essential for leukotriene synthesis. Its ability to reduce leukotriene production forms the basis for its therapeutic use in asthma. Previous in vitro and in vivo studies have suggested positive effects of both agents on bone tissue.
This study aimed to assess whether prophylactic treatment and combined administration of baicalein and zileuton could provide additional benefits for bone. An established ovariectomized rat model of postmenopausal osteoporosis was used, as it exhibits bone loss characteristics comparable to those seen in humans. The femur and lumbar vertebrae were selected for evaluation because they are among the most commonly affected sites of osteoporotic fractures.
Seventy female Sprague Dawley rats were randomized into five groups. At twelve weeks of age, 56 animals were ovariectomized to induce a postmenopausal osteoporotic state. Among these, one group received baicalein, another received zileuton, and a third received a combination of both agents, each administered via diet at a dosage of 10 mg/kg body weight. One ovariectomized group remained untreated, while a non-ovariectomized group served as healthy controls. Thirteen weeks after ovariectomy, serum, femora, and lumbar vertebrae were collected for analysis. Bone structure was assessed using 2D and 3D micro-CT. Biomechanical properties, such as stability and elasticity, were assessed through compression testing of the lumbar vertebrae and a three-point bending test of the femora. After ashing, the bones were analyzed to determine their organic and inorganic composition, along with phosphate, calcium, and magnesium content. Serum levels of alkaline phosphatase, osteocalcin, RatLaps, calcium, magnesium, and phosphorus were also evaluated. Statistical differences were assessed using one-way analysis of variance (ANOVA; p < 0.05) and Tukey–Kramer post hoc testing (p < 0.05).
The results of our study demonstrate that ovariectomy in rats leads to alterations in various parameters. Specifically, increases in body weight, food intake, and serum alkaline phosphatase were observed, while uterine weight and most bone parameters decreased. These changes are consistent with the expected effects of ovariectomy on bone properties in rats. The previously reported beneficial effects of baicalein and zileuton could not be confirmed under the conditions of extended treatment and prophylactic administration. Baicalein treatment led only to minor alterations, with a reduction in bone and trabecular volume. Zileuton showed similarly weak effects, reflected in an increased calcium-to-phosphate ratio in bone. Combined administration of baicalein and zileuton resulted in reductions in bone and cortical volume, cortical density, and the calcium-to-phosphate ratio. Most bone and serum parameters did not differ from the untreated OVX group. Notably, results from 2D micro-CT differed from those of 3D analysis; since 3D analysis considered the entire bone, these findings were prioritized in interpretation.
The lipoxygenase inhibitors had no observable effect on body weight, food intake, or uterine weight. Similarly, they did not influence the biomechanical properties of the bones.
In conclusion, prophylactic oral administration of the lipoxygenase inhibitors baicalein and zileuton, whether given individually or in combination, exerted only minor effects on femoral and vertebral bone tissue in ovariectomized rats. Moreover, combination therapy was associated with predominantly negative effects, indicating that these agents cannot be recommended for prophylactic treatment of osteoporosis. Future research should focus on the potential role of lipoxygenase inhibitors in chronic inflammation and associated markers in postmenopausal osteoporosis to better define the therapeutic window for their use.2025-12-2
Trans-ECMO thermodilution to measure recirculation during veno-venous Extracorporeal Membrane Oxygenation: an experimental animal study
No full textARDS is a syndrome responsible for an impressive morbidity and mortality. In the most severe cases, the lung function is so compromised that the oxygenation and decarboxylation provided are simply no more compatible with life. In other cases, the lung mechanics is so deranged that it is not possible to guarantee a sufficient gas exchange without directly injuring the lungs through the mechanical ventilation, the so-called VILI. In these selected cases, V-V ECMO is indicated as a last resort. V-V ECMO can provide an artificial and extracorporeal source of gas exchange allowing to uncouple the need of gas exchange of the patient from the minute ventilation provided by the ventilator. Unfortunately, the performance of the V-V ECMO can sometimes be unsatisfactorily. Many factors may be responsible, but a very important factor is, without doubt, the recirculation. Indeed, as in V-V ECMO the drainage and the return cannula lie in the same (central) venous district, there will always be a flow of blood from the return cannula that gets drained back into the ECMO device, instead of reaching the systemic circulation. Understanding the factors promoting the recirculation would be key to avoid it, as 100% recirculation implies the complete futility of the extracorporeal therapy. Unfortunately, recirculation is a phenomenon hard to study and, until now, most of the studies have been of computational nature, or using proprietary techniques. Recently, Cipulli and coworkers, however, showed in an in vitro study that a modification of a simple thermodilution technique, TET, applied on the extracorporeal circuit, can non-invasively and precisely estimate the recirculation fraction at the bedside. In this work, we applied the very same technique for the first time in vivo, in an animal study, to evaluate whether measuring the recirculation with TET is feasible outside an in vitro study and if the technique allows to measure the phenomenon at the bedside over time; to understand which are the determinants of the recirculation and if its values can be used in a mathematical algorithm to estimate the mixed venous oxygen content and saturation. Indeed, the gas composition in the pulmonary artery during V-V ECMO remains elusive if the patient is not equipped with a pulmonary artery catheter.
We studied 8 large pigs of 65 kg of weight. They were anesthetized, intubated and mechanically ventilated. Then they were instrumented with a standard set of intravascular catheters for the administration of drugs, fluids, blood sampling and measurements. The V-V ECMO was established with the cannulation of the femoral and jugular vein. A baseline measurement was acquired. The ARDS was induced in 4 animals with intratracheal instillations of hydrochloric acid and in 4 animals with the intravenous injection of oleic acid. The model was considered satisfactorily by a PaO2/FiO2 of 150 mmHg. After reaching the desired severity of the disease, the SGF was turned on and a set of measurements was acquired every 4 hours for 23 hours. At the end of the experiment the animals were sacrificed and the autopsy performed. The recirculation was studied throughout the duration of the experiment by TET.
ARDS was reached in all cases with both oleic and hydrochloric acid, and, despite the widely different methodology of application, the models were remarkably similar. Of note, ARDS induced with oleic acid was characterized by a more pronounced vascular permeability., However, it was more difficult to control. Recirculation was present in variable extent during the experiment. Some animals showed an elevated recirculation fraction throughout the experiment, while others showed very little recirculation. The proximity of the tip of the cannulas was not a relevant anatomical factor associated to the development of recirculation. Among the physiological factors, the most significant was the ratio between the extracorporeal blood flow and the cardiac output of the subject, which we named ExtraCorporeal Support fraction (ECSF). In other words, the higher the blood flow with respect to the cardiac output the higher the recirculation fraction. Using the value of recirculation we algorithmically estimated the mixed venous blood composition. We were able to estimate with a high degree of accuracy the mixed venous oxygen content and, to a lesser extent, even the mixed venous oxygen saturation.
The results of this study have a series of consequences. Firstly, we demonstrated that TET is easy, cost-effective and, above all, easy applicable at bedside. This is relevant, as the recirculation phenomenon has been elusive to quantify. Measuring it allowed to uncover some responsible variables and its consequences over the extracorporeal therapy. The fact that the ECSF is such a relevant variable is very important: indeed, while trying to improve the oxygenation performance of the ECMO, the clinician often increases the ECBF, with the aim to “treating” extracorporeally a larger fraction of the cardiac output. However, our study shows in vivo that this action also increases the recirculation, decreasing the effectiveness of the ECMO. Being able to measure the recirculation allows to directly find the ECMO setup that delivers the best performance in each individual patient.
Furthermore, being able to estimate the mixed venous oxygen content and saturation is potentially very important. The use of the pulmonary artery catheter is becoming increasingly rare, but this leaves the doctor blind to the composition of the blood in the pulmonary artery. Nevertheless, the oxygenation (and decarboxylation, for that matter) of the blood entering the pulmonary circulation is key to setup the ventilator during V-V ECMO. The better the mixed venous blood is oxygenated and decarboxylated, the more the patient is independent from the mechanical ventilation. We strongly believe that optimizing the gas exchange during V-V ECMO should be done by measuring the blood gas composition distal to the provided extracorporeal therapy, but before the mechanical ventilation takes place. Only by doing so the extracorporeal therapy and the ventilation can be understood independently and tweaked, if needed, accordingly.
Overall, recirculation is a pivotal variable for managing V-V ECMO. This insight allows V-V ECMO to be approached with greater precision rather than as an enigmatic "black box", ultimately enhancing patient safety.2026-01-0
Time Reversal Breaking and Entropy Production in Non-Equilibrium Systems: Insights from Mean Back Relaxation
No full textThe distinction between equilibrium thermal fluctuations, exemplified by Brownian motion, and active non-equilibrium processes is an essential problem in various fields of non-equilibrium statistical physics and biophysics. While Brownian motion is created by the random collision of a colloidal particle with much smaller surrounding particles, many biological and artificial systems exhibit externally and self-driven motion, for example, induced by external energy sources and molecular motors. This thesis addresses the problem of differentiating these motion types by focusing on the breaking of time reversal symmetry, a hallmark of non-equilibrium dynamics.
We investigate a novel quantity, the mean back relaxation (MBR), to detect said time reversal symmetry breaking. The mean back relaxation is a three point correlation function and is defined as the negative ratio of the displacement between to the displacement from . We find that the long time value of MBR approaches if later displacements get statistically independent from earlier ones, and if time reversal symmetry is valid. We demonstrate that MBR shows time reversal breakage for an active Brownian particle in a harmonic potential. We derive a solution for the finite time MBR for a Gaussian process in terms of the mean squared displacement (MSD) with a path integral formalism. This allows the analytic investigation of the time dependence of MBR curves in a Gaussian model. Also, we introduce a new density based MBR generalizing MBR to other types of observables. By analyzing the variance of the back relaxation (VBR), we characterize MBRs statistical properties and give estimates on how to select MBR parameters for practical applications.
Connecting MBR to fundamental concepts, we derive a new bound for entropy production, a central quantity in non-equilibrium dynamics. The bound is valid for time antisymmetric observables whose absolute value is bounded, and we find that the tightest observable is the sign of entropy production. This leads to an interesting coarse graining scheme that leaves the bound intact by grouping paths according to their stochastic entropy production. We test the entropy bound for a time discrete ring and compare it to other known relations.
We apply MBR to experimental data obtained from colloidal particles in living cells. We can qualitatively reconstruct the curves found from cell data with a Random Horse and Cart model. Both in the model and cell data for different cell types, the long time value of MBR is linearly related to effective energy amplitude, which quantifies the violations of the fluctuation dissipation theorem (FDT), a common indirect marker of breaking of time reversal symmetry.
Finally, we test the time reversal properties of MBR for cell data. We show that for colloidal particles in cells, MBR detects breaking of time reversal symmetry. This is one of the first direct empirical evidences for observable time reversal breaking of colloidal particles in living cells. The time reversal breaking is greatly reduced by depolymerization of microtubules, which hints that the effect is linked to cytoskeletal activity. We also apply the entropy production bound by inserting the anti-symmetric part of MBR and find that the lower bound given by MBR is correlated to FDT violations for different cell types, quantified by the effective energy amplitude.2025-11-2
Development of ¹⁹F and ³¹P Dynamic Nuclear Polarization in the Liquid State
No full textWithin the last decades, nuclear magnetic resonance (NMR) spectroscopy in the liquid state has become one of the most powerful techniques allowing for the analysis of structures and dynamics of chemical systems at atomic scale. Regardless of its immense value, NMR is yet vastly limited because of its inherent low sensitivity arising from the small population difference of the nuclear spin states. Overhauser effect dynamic nuclear polarization (OE-DNP) is a hyperpolarization method that aims at enhancing the sensitivity of NMR spectroscopy in the liquid state. Here, the magnetization from higher polarized electron spins is exploited by transfer onto the target nuclei of interest under microwave irradiation at the electron spin Larmor frequency.
While the implementation of liquid state OE-DNP for the common ¹H and ¹³C nuclei is ongoing, the focus of this thesis is the development and investigation of ¹⁹F and ³¹P nuclei, that both also find relevant application areas in NMR spectroscopy. It is important to expand the range of target nuclei to reveal the OE-DNP capabilities in the liquid state.
Previous insights show that the chemical structure of the polarizing agent and target molecule as well as their interaction dynamics play a decisive role in OE-DNP. Because of this and as large NMR signal enhancements are desired for any magnetic fields, a thorough understanding of the underlying DNP mechanism is necessary. The investigation of the field dependence on the DNP performance is the most reliable way to achieve this goal.
Therefore, these target nuclei were investigated at low (¹⁹F and ³¹P) and high magnetic fields (¹⁹F) of 1.2 and 9.4 Tesla with different types of polarizing agents. The obtained results were complemented with reported data from the literature at various magnetic field strengths. With this, the field dependence on the DNP efficiency was fitted showing different performances on the type of target nucleus and employed polarizing agent and the simulations offered insights into the molecular dynamics of the radical-target molecule interaction. The experimental findings were rationalized with the help of density functional theory (DFT) calculations. The results show that weak non-covalent radical-target interactions enable an efficient polarization transfer mediated by lone pair electrons of the ¹⁹F and ³¹P nuclei.
Besides the new mechanistic insights into ¹⁹F and ³¹P OE-DNP, considerable ¹⁹F-NMR enhancements on a variety of fluorinated target molecules were obtained at 9.4 T. Moreover, the large generated hyperpolarization on ¹⁹F can be distributed to coupled nuclei in the target molecule in 1D and 2D polarization transfer experiments, paving the way towards possible applications.2025-12-0
Community assembly processes of intertidal salt marsh microarthropods
No full textSalt marshes are highly dynamic ecosystems at the land–sea interface, shaped by steep environmental gradients and frequent disturbances. They provide critical ecosystem services, including coastal protection, nutrient cycling and biodiversity maintenance, while also serving as natural laboratories for studying how dispersal, environmental filtering and competitive
interactions structure ecological communities. Among the diverse organisms inhabiting these systems, microarthropods such as Collembola, Oribatida and Mesostigmata are both abundant and ecologically important, contributing to decomposition, nutrient cycling and food-web regulation. Despite their ubiquity and functional importance, the mechanisms underlying their
colonization, persistence and assembly in intertidal salt marshes remain poorly understood.
Ecological theory emphasizes two broad categories of processes in community assembly: deterministic and stochastic. Deterministic forces, including environmental filtering and competitive interactions, predictably structure communities along abiotic gradients such as tidal inundation or salinity. By contrast, stochastic forces such as dispersal limitation, ecological drift and historical contingency introduce randomness into community formation. The relative importance of these processes often depends on spatial scale, disturbance frequency and habitat connectivity. In salt marshes, where tidal regimes and geographic isolation constrain colonization opportunities, both deterministic and stochastic influences are strong.
This thesis investigates how dispersal, environmental gradients and functional adaptations structure salt marsh microarthropod communities in the Wadden Sea, Germany. Using experiments on natural shorelines and isolated artificial offshore islands, it explores colonization dynamics, trait-mediated persistence and the relative influence of deterministic versus stochastic assembly processes across taxa and spatial contexts.
The first chapter examines colonization across tidal zones and offshore artificial islands, testing how dispersal distance, inundation frequency and body size influence community assembly. Results show that dispersal limitation and filtering due to inundation frequency differently affect Collembola, Oribatida and Mesostigmata, with Oribatida emerging as particularly poor and Mesostigmata as particularly effective colonizers.
The second chapter adopts a trait-based perspective, harmonizing morphological and functional traits across taxa to evaluate whether analogous traits buffer species against extinction. Traits related to anchoring, buoyancy and hydrophobicity were shown to mitigate displacement and extinction under frequent inundation, revealing convergent strategies that stabilize communities despite phylogenetic differences.
The third chapter focuses on predatory Mesostigmata, integrating phylogenetic and trait-based analyses to disentangle deterministic and stochastic influences across tidal inundation gradients and geographic isolation. The findings demonstrate that deterministic filters dominate in connected systems, while stochasticity prevails in isolated ones, underscoring the dual roles of dispersal and environmental stress in shaping intertidal predator communities.
Collectively, these studies advance understanding of how dispersal, environmental filtering and functional traits interact to structure ecological communities in disturbance-prone environments. By combining colonization experiments, trait harmonization and phylogenetic analysis, this thesis contributes to theoretical ecology and trait-based community assembly research, while offering new insights into the resilience and vulnerability of salt marsh microarthropod communities under global change.2025-12-0
An Empirically Informed Analysis of the Medical Concept of Quality of Life in Cardiology
No full textBackground: Quality of life is established in medicine as one of three legally defined endpoints and is typically assessed from the patient’s perspective across physical, psychological, and social dimensions. However, this health-related operationalization proves insufficient, particularly in the context of chronic illness. In such cases, physical limitations, psychological burdens, and social challenges become integral parts of everyday life and significantly influence how life is shaped. Individual preferences, the pursuit of goals, and the experience of meaning gain importance – dimensions more closely aligned with broader understandings of quality of life, such as those promoted by the WHO.
Objective: This study aims to identify core aspects of a good life in the context of chronic heart disease in order to expand the measurement of health-related quality of life and bridge the gap between conceptual understanding and practical operationalization.
Methods: The study combines conceptual and empirical approaches. First, the relationship be-tween quality of life and a good life is analyzed from a theoretical-methodological perspective to identify shortcomings in current measurement practices. This is followed by a systematic meta-synthesis of international qualitative studies on patient-centered concepts to uncover implicit aspects of a good life in the context of chronic heart disease. Due to the limited number of relevant studies in Germany, an additional qualitative study was conducted with affected adults in this country. Both studies use Interpretative Phenomenological Analysis (IPA; Smith et al. 2022).
Results: Findings indicate that aspects of a good life correspond to the familiar dimensions (physical, psychological, social) but exhibit a more existential depth. Regaining a fundamental sense of bodily trust – enabling interaction with the world – is central. Interpersonal relation-ships are not only experienced as sources of practical and emotional support but also as sources of meaning that may deepen through illness. A key theme is the need for self-determination – to actively shape one’s life rather than be defined by the illness. This often relates to the desire to restore a sense of normality and align one’s self-image with previous conceptions of self. At the same time, patients report that acceptance is an essential element of a good life: the ability to integrate new qualities into the self and grow through the illness. This can lead to a renewed appreciation for life itself. Temporal aspects also emerge as significant – such as the loss of temporal autonomy and the experience of biographical disruption due to the sudden onset of illness.
Conclusions: The results reveal that, in addition to physical, mental, and social well-being and functioning, existential and meaning-related dimensions are equally important for living a good life with chronic heart disease. Future research should more strongly incorporate these perspectives. In practice, this means supporting patients not only with symptom management but holistically – considering their life goals, autonomy, and need for meaning.2026-01-1
Collaborative Learning with Virtual Reality: A Classroom Perspective
No full textMit der zunehmenden Zugänglichkeit des Metaverse und seiner damit verbundenen Technologien erkennen Lehrkräfte aus verschiedenen Disziplinen zunehmend deren Potenzial zur Förderung von Lernprozessen. Virtual-Reality- (VR-)Technologien bieten immersive Umgebungen, die auf spezifische Lernziele zugeschnitten sind, und ermöglichen es Lernenden, sich interaktiv mit Zielinhalten in virtuellen Umgebungen auseinanderzusetzen sowie authentische Erfahrungen in Bezug auf Kultur, Sprache, Geografie und weitere Bereiche zu machen. Mit der Weiterentwicklung digitaler Bildungsmedien ist es möglich, unterschiedliche Werkzeuge einzusetzen, um eine verkörperte kollaborative Lernumgebung (Collaborative Learning, CL) für Lernende zu gestalten. Eine ausschließliche Fokussierung auf den Einsatz von Technologie garantiert jedoch keine erfolgreichen Lernergebnisse. Über die Technologie hinaus spielen Faktoren wie Lernstrategien, Scaffolding und die pädagogische Begleitung durch Lehrkräfte eine entscheidende Rolle für die Förderung von tiefem Lernen und effektivem kollaborativem Lernen.
Diese Studie untersucht die Umsetzung von VR-gestütztem kollaborativem Lernen in realen Unterrichtskontexten und nicht unter kontrollierten Laborbedingungen. Im Gegensatz zu Laborstudien, in denen häufig einzelne Variablen isoliert betrachtet werden, verdeutlicht Forschung in authentischen Klassenzimmern die Komplexität und die Herausforderungen der Integration von VR in die Unterrichtspraxis. Anhand von Beispielen aus dem Geschichts-, Geografie- und Fremdsprachenunterricht untersucht die Studie in drei Teilstudien, wie immersive Technologien kollaboratives Lernen durch eine doppelte Fokussierung auf technologische und pädagogische Strategien fördern können. Dieser Ansatz macht die Vielschichtigkeit der VR-Integration im Bildungsbereich sichtbar und unterstreicht die Bedeutung der Berücksichtigung praktischer und kontextueller Faktoren, um nachhaltige Lernergebnisse zu erzielen.
Die erste Teilstudie untersucht, wie unterschiedliche Immersionsgrade im VR-gestützten Unterricht den Erwerb historischer Empathie beeinflussen. Dabei wird das Konzept der „physischen Empathie“ erstmals in den Kontext immersiver Unterrichtsumgebungen eingeführt und angewendet und stellt somit einen originellen Beitrag zur Forschung dar. Es wurde ein quasi-experimentelles Design gewählt, das quantitative und qualitative Methoden kombinierte, um die Entwicklung historischen Wissens und historischer Empathie der Teilnehmenden zu analysieren. Die Ergebnisse zeigten keine statistisch signifikanten Unterschiede im Erwerb historischen Wissens zwischen Schülerinnen und Schülern, die immersive Virtual Reality (IVR) nutzten, und jenen, die mit Flatscreen-VR arbeiteten. Qualitative Daten deuteten jedoch darauf hin, dass Lernende in der IVR-Gruppe stärkere Ausprägungen „physischer Empathie“ zeigten. Interessanterweise berichteten die Lernenden trotz fehlender messbarer Wissenszuwächse im IVR-gestützten Lernen subjektiv, effektiver gelernt zu haben. Dies verdeutlicht den Einfluss von IVR auf die subjektive Lernerfahrung im Unterricht.
Die zweite Teilstudie stellt einen Ansatz für immersive virtuelle Exkursionen vor, der darauf abzielt, Lernenden eine verkörperte Lernerfahrung zu ermöglichen und durch kollaborative Lernstrategien die Interaktion unter Peers zu fördern. In einem quasi-experimentellen Design wurden die Effekte dieses Ansatzes mit einer konventionellen technologiegestützten Methode im Geografieunterricht verglichen. Die Ergebnisse zeigen, dass der Ansatz der immersiven virtuellen Exkursionen die Peer-Interaktion, die Kooperationsbereitschaft sowie die Wahrnehmung medialer Unterstützung signifikant verbesserte, während keine signifikanten Effekte auf die Lehrer-Schüler-Interaktion oder die schulischen Leistungen festgestellt wurden. Darüber hinaus verdeutlichten Interviewdaten die positiven Wahrnehmungen der Lernenden. Sie beschrieben den Ansatz als „verantwortungsvoll und unterhaltsam“, „verständlich und produktiv“, mit „besserer Visualisierung“ sowie als förderlich für eine „einfache Kommunikation“ innerhalb von Gruppen. Diese subjektiven Wahrnehmungen liefern wertvolle Einblicke in die emotionalen Erfahrungen der Lernenden und deren Interaktion mit IVR-gestützten Lernprozessen im realen Unterricht. Sie bieten einen wichtigen Kontext für die Interpretation quantitativer Ergebnisse und für zukünftige Gestaltungsverbesserungen IVR-gestützter Unterrichtsumgebungen.
Die dritte Teilstudie präsentiert einen Ansatz mit einer virtuellen Klassenraumkarte, der darauf abzielt, eine Kultur des Wissensaustauschs (Knowledge Sharing, KS) zu fördern und gleichzeitig Lehrkräfte bei der Beobachtung von Gruppenarbeit sowie der Bereitstellung von Feedback im IVR-gestützten kollaborativen Lernen zu unterstützen. Ein randomisiertes Crossover-Design wurde eingesetzt, um zwei Bedingungen im Englisch-als-Fremdsprache-Unterricht (EFL) zu vergleichen: den IVR-Lernansatz mit virtueller Klassenraumkarte (MIVRL) und den IVR-Lernansatz ohne virtuelle Klassenraumkarte (IVRL). Die Analyse ergab drei zentrale Ergebnisse: (1) Der MIVRL-Ansatz verbesserte die inhaltliche Leistung der Lernenden bei Schreibaufgaben signifikant im Vergleich zum IVRL-Ansatz. (2) Trotz der technischen Komplexität hielt der MIVRL-Ansatz das Interesse der Lernenden aufrecht und erhöhte nicht ihre Versagensängste. (3) Der vorgeschlagene MIVRL-Ansatz zeigte das Potenzial, VR zu einem Werkzeug zu machen, das eine „Kultur des Teilens“ im formalen Bildungsbereich stärkt. Diese Ergebnisse unterstreichen den Mehrwert innovativer Werkzeuge wie der virtuellen Klassenraumkarte zur Förderung kollaborativen Lernens und einer Wissensaustauschkultur in bildungsbezogenen Kontexten, die auf Austausch und Feedback ausgerichtet sind.
Diese Arbeit nutzt unterschiedliche VR-gestützte Endgeräte und immersive virtuelle Lernmaterialien, um zu untersuchen, wie verschiedene VR-Technologien, Formen des Scaffoldings und pädagogische Strategien Lernprozesse und Lernergebnisse in realen Unterrichtskontexten beeinflussen. Die Ergebnisse liefern wertvolle Erkenntnisse zur Integration immersiver Bildungstechnologien im Klassenzimmer und verdeutlichen das Zusammenspiel zwischen technologischen Affordanzen und pädagogischen Strategien. Durch die Kombination immersiver Lernumgebungen mit gezielt eingesetzten Lernstrategien und Scaffolding zeigt die Studie, wie verbessertes kollaboratives Lernen bedeutungsvolle Interaktionen fördert und die affektiven Lernerfahrungen der Lernenden in VR-gestützten Unterrichtsszenarien verbessert. Insgesamt bietet diese Arbeit einen Rahmen zur Neugestaltung der Konzeption und Umsetzung von VR-gestütztem kollaborativem Lernen im realen Unterricht, indem sie die Notwendigkeit betont, technologische Innovationen – einschließlich technologischer Weiterentwicklungen und innovativer Nutzung – mit praxisnahen Unterrichtsstrategien und Lernunterstützung zu verknüpfen, um nachhaltigere und wirkungsvollere Bildungsergebnisse zu erzielen.As the Metaverse and its associated technologies become more accessible, educators across various disciplines increasingly recognize their potential for enhancing learning. Virtual reality (VR) technology offers immersive environments tailored to specific learning objectives, allowing learners to engage interactively with target content in virtual environments and facilitating authentic experiences related to culture, language, geography, and more. With the development of educational media, it is possible to adopt various tools to create an embodied collaborative learning (CL) environment for learners. However, focusing solely on the use of technology does not guarantee successful learning outcomes. Beyond the technology itself, factors such as learning strategies, scaffolding, and teacher facilitation play a crucial role in fostering deep learning and effective collaborative learning.
This study examines the implementation of VR-supported CL in real-world classroom settings rather than controlled laboratory conditions. Unlike laboratory studies, which often isolate variables, research conducted in authentic classroom environments highlights the complexities and challenges of integrating VR into practice. Using examples from history, geography, and second language learning, the study explores how immersive technologies can enhance CL through a dual focus on technological and pedagogical strategies through three sub-studies. This approach sheds light on the multifaceted nature of VR integration in education and underscores the importance of addressing practical, contextual factors to achieve meaningful learning outcomes.
The first sub-study focuses on examining how different levels of immersion in VR-supported classroom learning influences the acquisition of historical empathy. This study introduces and applies the concept of ‘physical empathy’ within the context of immersive classroom environments, representing an original contribution to the field. A quasi-experimental design was employed, which combined quantitative and qualitative methods to investigate participants’ development of historical knowledge and empathy. The findings revealed no statistically significant differences in historical knowledge acquisition between students using immersive virtual reality (IVR) and those using flatscreen VR. However, qualitative data indicated that students in the IVR group demonstrated stronger manifestations of ‘physical empathy.’ Interestingly, despite the lack of measurable knowledge gains in IVR-supported learning, students self-reported perception of learning more effectively in this immersive classroom setting, which highlights the subjective impact of IVR on their educational experience.
The second sub-study introduces an immersive virtual field trip approach, which is designed to provide students with an embodied learning experience and is complemented by CL strategies to foster peer interaction. A quasi-experiment was conducted to compare the effects of the proposed approach with a conventional technology-supported method in a geography classroom. The findings reveal that the immersive virtual field trip approach significantly enhanced students’ peer interaction, collaboration tendencies, and perceptions of media support, while no significant improvements were observed in teacher-student interaction or academic achievements. Moreover, interview data highlighted students’ positive perceptions of the approach. They described it as being “responsible and enjoyable,” “understandable and productive,” offering “better visualization,” and enabling “easy communication” among peers and groups. These subjective perceptions are valuable as they provide insight into students’ emotions and IVR-supported real classroom interaction with the learning process. This offers important context for interpreting quantitative results and guiding future design improvements in IVR-supported classroom environments.
The third sub-study presents a classroom map approach, which is aimed at fostering a knowledge-sharing (KS) culture while simultaneously supporting teachers in monitoring group work and helping students receive feedback during IVR-supported CL. A randomized crossover design was implemented to compare two conditions in an English as a Foreign Language (EFL) classroom: the virtual classroom map-supported IVR learning approach (MIVRL) and the IVR learning approach without the virtual classroom map (IVRL). The analysis yielded three key findings: (1) The MIVRL approach significantly improved students’ content performance on writing tasks compared to the IVRL approach. (2) Despite its technical complexity, the MIVRL approach maintained students’ interest and did not increase their fear of failure. (3) The proposed MIVRL approach demonstrated the potential to transform VR into a tool that reinforces a “culture of sharing” in formal education. These results highlight the value of integrating innovative tools like the virtual classroom map to enhance CL and promote a KS culture in educational contexts that emphasize sharing and feedback.
This research utilizes different VR-enabled devices and immersive virtual learning materials to explore how various VR technologies, scaffolding, and strategies influence learning processes and outcomes in real classroom settings. The findings offer valuable insights into the integration of immersive educational technology in classroom settings, highlighting the interplay between technological affordances and pedagogical strategies. By combining immersive environments with tailored learning strategies and scaffolding, this study demonstrates how enhanced CL fosters meaningful interactions, and improve learners’ affective experiences in VR-supported classrooms. Ultimately, this work provides a framework for rethinking the design and implementation of VR-supported CL in real classrooms: emphasizing the need to align technological innovations including technology updates and innovational use with practical teaching strategies and learning scaffolding to achieve more impactful educational outcomes.2026-02-0
Quantification and optimization of mixing efficiency in active microfluidic systems
No full textMixing at the microscale is a fundamental process in biological systems and microfluidic technologies, yet it remains challenging due to the kinematic reversibility of low–Reynolds-number flows, where viscous forces dominate and inertial effects are negligible. Efficient mixing in such systems relies on a subtle interplay between advection and diffusion, and its quantification depends sensitively on the choice of mixing metric.
In this thesis, a universal and assumption-free framework for quantifying mixing efficiency in viscous fluids is developed based on mutual information between the initial and final positions of fluid particles. Interpreting mixing as a process of information loss, mutual information provides a global measure of mixing that is independent of imposed solute distributions and applicable to general advection–diffusion systems.
The approach is first validated in a two-dimensional Taylor–Couette flow, where the advection–diffusion equation is solved using spectral methods and Brownian dynamics simulations. The decay of mutual information is used to compare different mixing protocols and to identify optimal strategies. It is shown that non-uniform rotation sequences can significantly enhance mixing efficiency compared to uniform protocols at fixed rotation or dissipation. Mutual information is further compared with conventional measures such as concentration variance, highlighting its robustness and universality. Complementary techniques, including data-compression-based estimators and Taylor-dispersion analysis, are introduced to provide alternative routes for estimating mutual information in complex flows.
The framework is then extended to active microfluidic systems driven by micro-swimmers. Using multipole expansions for swimmer-induced Stokes flows in free space and confined geometries, the mixing efficiency generated by different swimmer configurations is quantified. For a fixed rate of viscous dissipation, the results identify optimal swimmer types and spatial arrangements that maximize mixing.
Overall, this thesis demonstrates that mutual information provides a natural and universal framework for quantifying and optimizing mixing in viscous and active fluid systems. By recasting mixing as an irreversible process of information loss, the approach transcends traditional pattern-dependent measures and unifies passive and active mixing within a single theoretical perspective rooted in information theory. Beyond its immediate applications to microfluidic and swimmer-driven flows, this framework opens new avenues for the systematic design and control of nonequilibrium transport processes in soft and biological matter.2026-02-1
The inward rectifying potassium currents IK1 and IK,ACh in atrial cardiomyocytes from human induced pluripotent stem cells and their remodeling under in vitro field stimulation
No full textVorhofflimmern ist die häufigste anhaltende supraventrikuläre Herzrhythmusstörung des Menschen und ist mit einer immensen Erhöhung des Schlaganfallrisikos assoziiert. Noch immer sind viele Kernfragen zur Entstehung und damit auch zur zielgerichteten Behandlung dieser Erkrankung unverstanden. Tiermodell vermochten es bisher auf Grund der interspezifischen Unterschiede der elektrophysiologischen Eigenschaften nicht diese zu beantworten. Kardiomyozyten aus induzierten pluripotenten Stammzellen haben sich im letzten Jahrzehnt zu einem vielversprechenden Werkzeug in der kardiovaskulären Forschung entwickelt. Ein auf iPSC-Kardiomyozyten atrialen Phänotyps basiertes Zellmodell könnte helfen diese Krankheit besser zu verstehen und damit den Weg für neue Behandlungsmöglichkeiten ebnen. Hierzu wurden iPSC-Kardiomyozyten mit Retinsäure behandelt um anschließend mit der Voltage-Clamp Methode den basalen einwärtsgleichgerichteten Kaliumstrom IK1 und den atrial spezifischen Acetylcholin aktivierten Strom IK,ACh zu untersuchen. Als Kontrolle dienten dabei iPSC-Kardiomyozyten ventrikulärer Differenzierung. In einem zweiten Schritt wurden diese atrialen iPSC-KMs im Rahmen von in-vitro Tachypacing Experimenten auf Veränderungen dieser Ströme untersucht und diese vor dem Hintergrund des atrialen Remodellings bei Vorhofflimmern beurteilt. Der durch ein rampenförmiges Spannungsprotokoll von -100 mV bis -40 mV hervorgerufene Barium-sensitive Basalstrom (IK1) zeigte keinen signifikanten Unterschied zwischen den beiden Phänotypen. Dafür zeigte sich in den atrialen IPSC-KMs ein deutliche Stromzunahme durch Carbachol (2 µM; IK,ACh), während weniger als 10% der ventrikulären Zellen (3/32) eine Stromzunahme zeigten, was sich mit der 90% Reinheit des ventrikulären Phänotyps aus anderen Arbeiten deckt. In isolierten Zellen aus einem auf atrialen iPSC-Kardiomyozyten basierten Gewebemodell (EHM) zeigte sich, dass, sowohl IK1 als auch IK,ACh konserviert bleiben und in gleicher Weise in diesen Zellen exprimiert werden. Der konzentrationsabhängig durch Carbachol aktivierte IK,ACh zeigte den gleichen charakteristischen in humanen Kardiomyozyten beschriebenen Verlauf mit einem Peak- und einem QSS Strom und einer Abnahme der Stromzunahme bei wiederholter Aktivierung. Weiterhin konnte weder in der Anwesenheit des M-Rezeptor-Blockers Atropin (1 µM) noch in Anwesenheit des selektiven IK,ACh-Blockers Tertiapin (100nM) eine Stromzunahme durch Carbachol induziert werden, was zeigt, dass IK,ACh wie in humanem Gewebe über einen muskarinergen Acetylcholinrezeptor aktiviert und durch einen so genannten GIRK-Kanal vermittelt wird. Da der Basalstrom unter Tertiapin unverändert blieb kann ferner davon ausgegangen werden, dass dieser wie unter physiologischen Bedingungen nur von IK1 gebildet wird und dass es keine Rezeptor-unabhängige Aktivität von IK,ACh gibt. Neben Carbachol konnte wie in humanen atrialen Kardiomyozyten auch Adenosin (1 mM) konzentrationsabhängig eine Stromzunahme entsprechend IK,ACh induzieren (hier IK,Ado). Es konnte gezeigt werden, dass in-vitro Tachypacing mit 3 Hz im Vergleich zu einer 1 Hz – Kontrollgruppe suffizient ist, Veränderungen des IK,ACh zu induzieren. Während nach einem Stimulationszeitraum von 15 h noch keine signifikanten Veränderungen beobachtet werden konnten, so konnte nach 24 h eine schwache Tertiapin-sensitive Komponente des Basalstroms gemessen werden. Ein Wechsel des Zellmediums während der Stimulation mit einer Erhöhung des Calciumgehalts von 0,42 auf 1,8 mM führte schließlich zu einer signifikanten Reduktion sowohl von Peak- und QSS- IK,ACh sowie zu einer Tertiapin-sensitiven Komponente des Basalstroms von fast 30%. Obwohl für den absoluten Basalstrom bisher unter keiner der Stimulationsbedingungen eine signifikante Veränderung erzeugt werden konnte, so sprechen die beschriebenen Veränderungen von IK,ACh für ein potenziell Calcium-abhängiges Remodelling wie es in humanen Zellen von Patienten mit paroxysmalem oder chronischem Vorhofflimmern beschrieben wurde. Eine große Stärke der iPSC-Kardiomyozyten ist, dass sie im Gegensatz zu humanen Kardiomyozyten langfristig in Kultur gehalten werden können. So war es mit diesen Zellen möglich die Erholung vom Tachypacing zu untersuchen. Es zeigte sich, dass die induzierten Veränderungen des IK,ACh potenziell reversibel sind, so dass das vorliegende Zellmodell geeignet scheint die zeitlichen Abläufe des Remodellings von VHF genauer zu untersuchen. Die Arbeit zeigt, dass aus humanen pluripotenten Stammzellen generierte Kardiomyozyten atrialen Phänotyps einen funktionellen, stabilen IK,ACh exprimieren und das in einer Größenordnung, die die Untersuchung und Induktion von Veränderungen des Stromes möglich macht. Mittels in-vitro Tachypacings konnte in iPSC-Kardiomyozyten das IK,ACh bezogene Remodelling des VHF repliziert werden und in einem nächsten Schritt wieder rückgängig gemacht werden. Hieraus ergibt sich ein vielversprechendes Zellmodell, welches in einem weiteren Schritt als Grundlage für ein auf iPSC-Kardiomyozyten basiertes Gewebemodell (EHM) dienen soll und damit die Untersuchung des Tachypacing-induzierten Remodellings unter Berücksichtigung der physiologischen Zell-Zell-Interaktion, sowie die Anwendung weiterer Untersuchungsmethoden und (pharmakologischen) Testungen möglich macht.Atrial fibrillation is the most common sustained supraventricular arrhythmia in humans and is associated with an immense increase in the risk of stroke. Many key questions about the development and therefore also the targeted treatment of this disease are still not understood. So far, animal models have not been able to answer these questions due to the interspecific differences in electrophysiological properties. Cardiomyocytes from induced pluripotent stem cells have developed into a promising tool in cardiovascular research over the last decade. A cell model based on iPSC cardiomyocytes of atrial phenotype could help to better understand this disease and thus pave the way for new treatment options. To this end, iPSC cardiomyocytes were treated with retinoic acid and then the basal inward rectifying potassium current IK1 and the atrial specific acetylcholine activated current IK,ACh were analyzed using the voltage-clamp method. iPSC cardiomyocytes of ventricular differentiation served as control. In a second step, these atrial iPSC-KMs were examined for changes in these currents in the context of in-vitro tachypacing experiments and assessed against the background of atrial remodeling in atrial fibrillation. The barium-sensitive basal current (IK1) elicited by a ramped voltage protocol from -100 mV to -40 mV showed no significant difference between the two phenotypes. On the other hand, in the atrial IPSC-KMs, carbachol (2 µM; IK,ACh) showed a clear current increase, whereas less than 10% of the ventricular cells (3/32) showed a current increase, which is consistent with the 90% purity of the ventricular phenotype from other studies. In isolated cells from an atrial iPSC cardiomyocyte-based tissue model (EHM), both IK1 and IK,ACh were shown to be conserved and equally expressed in these cells. IK,ACh activated by carbachol in a concentration-dependent manner showed the same characteristic course described in human cardiomyocytes with a peak and a QSS current and a decrease in current increase with repeated activation. Furthermore, neither in the presence of the M-receptor blocker atropine (1 µM) nor in the presence of the selective IK,ACh blocker tertiapine (100nM) could a current increase be induced by carbachol, indicating that IK,ACh is activated via a muscarinic acetylcholine receptor as in human tissue and mediated by a so-called GIRK channel. Since the basal current remained unchanged under tertiapine, it can also be assumed that it is only formed by IK1 as under physiological conditions and that there is no receptor-independent activity of IK,ACh. In addition to carbachol, adenosine (1 mM) was also able to induce a concentration-dependent increase in current corresponding to IK,ACh (here IK,Ado), as in human atrial cardiomyocytes. It could be shown that in-vitro tachypacing at 3 Hz is sufficient to induce changes in IK,ACh compared to a 1 Hz control group. While no significant changes could be observed after a stimulation period of 15 h, a weak tertiapine-sensitive component of the basal current could be measured after 24 h. A change of the cell medium during stimulation with an increase of the calcium content from 0.42 to 1.8 mM finally led to a significant reduction of both peak and QSS- IK,ACh as well as to a tertiapine-sensitive component of the basal current of almost 30%. Although no significant change in the absolute basal current could be generated under any of the stimulation conditions, the described changes in IK,ACh suggest a potential calcium-dependent remodeling as described in human cells from patients with paroxysmal or chronic atrial fibrillation. A major strength of iPSC cardiomyocytes is that, unlike human cardiomyocytes, they can be kept in culture for long periods. It was therefore possible to use these cells to investigate recovery from tachypacing. It was shown that the induced changes in IK,ACh are potentially reversible, so that the present cell model seems suitable for investigating the temporal processes of remodeling of VHF in more detail. The work shows that cardiomyocytes generated from human pluripotent stem cells of atrial phenotype express a functional, stable IK,ACh at a level that allows the investigation and induction of changes in the current. Using in vitro tachypacing, the IK,ACh-related remodeling of VHF could be replicated in iPSC cardiomyocytes and reversed in a next step. This results in a promising cell model, which in a further step should serve as the basis for a tissue model (EHM) based on iPSC cardiomyocytes and thus enable the investigation of tachypacing-induced remodeling, taking into account the physiological cell-cell interaction, as well as the application of further investigation methods and (pharmacological) tests.2025-05-0
Results of the Diast-CHF Study
No full textInsgesamt wurden 851 Patienten aus der DIAST-CHF Studie auf ihr Outcome nach fünf Jahren untersucht. Die Patienten wiesen mindestens einen Risikofaktor für die Entwicklung einer Herzinsuffizienz auf, hatten aber zu Beginn keine Zeichen oder Symptome einer Herzinsuffizienz. Alle Patienten wurden anhand der aktuellen Empfehlungen der European Society of Cardiology auf das Vorliegen einer HFpEF untersucht (Paulus et al. 2007). Dabei erfolgte eine Aufteilung in eine Gruppe mit hämodynamisch relevanter DD (n = 181) und eine Gruppe ohne DD (n = 670). Die Gruppen wurden hinsichtlich ihrer klinischen und soziodemographischen Parameter miteinander verglichen. Diese Parameter und das Erfüllen der Kriterien des Algorithmus zur Abklärung der HFpEF der working group der ESC nach Paulus, die eigentlich bei symptomatischen Patienten zur Diagnostik eingesetzt werden, wurden in diesem Zusammenhang erstmals hinsichtlich der Entwicklung einer DD in eine HFpEF untersucht. Es konnten klinische und soziodemographische Parameter ermittelt werden, die unabhängige Prädiktoren für die Entwicklung einer HFpEF bilden, nämlich das Alter, das weibliches Geschlecht, eine bekannte koronare Herzkrankheit sowie die Blutdruckamplitude. „DD positiv“ erwies sich dabei allerdings nicht als unabhängiger Prädiktor für die Gesamtsterblichkeit oder die kardiovaskulär bedingte Hospitalisierung. Ohne Adjustierung zeigte sich eine ca. doppelt erhöhte Hazard Ratio. Bei einer Adjustierung für Alter, weibliches Geschlecht, bekannte KHK, Blutdruckamplitude und Herzfrequenz nahm die Hazard Ratio ab und zeigte dann auch keine Signifikanz mehr. Allerdings erwies sich „DD positiv“ als unabhängiger Prädiktor für die Gesamtsterblichkeit, die kardiovaskuläre Hospitalisierung und das Auftreten von Symptomen bzw. Zeichen der Herzinsuffizient als gemeinsamer Endpunkt. Nach der Adjustierung lag die Odds Ratio als Assoziationsmaß bei 1.48 (p = 0.041). Ein weiteres interessantes Ergebnis war der Langzeitverlauf nach fünf Jahren. Bei Patienten mit hämodynamisch relevanter DD konnten signifikant mehr Herzinsuffizienzsymptome nachgewiesen werden. Besonders bei Dyspnoe und peripheren Ödemen zeigten sich deutliche Unterschiede zwischen den beiden Gruppen. Andere Symptome der Herzinsuffizienz waren dagegen in keiner der beiden Gruppen wesentlich stärker vertreten.A total of 851 patients from the DIAST-CHF study were examined for their five-year outcome. The patients had at least one risk factor for the development of heart failure, but had no signs or symptoms of heart failure at baseline. All patients were examined for the presence of HFpEF according to the current recommendations of the European Society of Cardiology (Paulus et al. 2007). They were divided into a group with hemodynamically relevant DD (n = 181) and a group without DD (n = 670). The groups were compared with regard to their clinical and sociodemographic parameters. These parameters and fulfillment of the criteria of the algorithm for the evaluation of HFpEF of the ESC working group according to Paulus, which are actually used for diagnostic purposes in symptomatic patients, were examined for the first time in this context with regard to the development of DD into HFpEF. Clinical and sociodemographic parameters were identified that are independent predictors of the development of HFpEF, namely age, female sex, known coronary artery disease, and blood pressure amplitude. However, "DD positive" did not prove to be an independent predictor of overall mortality or cardiovascular-related hospitalization. Without adjustment, the hazard ratio was approximately twice as high. When adjusted for age, female sex, known coronary artery disease, blood pressure amplitude, and heart rate, the hazard ratio decreased and then no longer showed significance. However, "DD positive" proved to be an independent predictor of overall mortality, cardiovascular hospitalization, and the occurrence of symptoms or signs of heart failure as a common endpoint. After adjustment, the odds ratio as a measure of association was 1.48 (p = 0.041). Another interesting finding was the long-term follow-up after five years. Patients with hemodynamically relevant DD had significantly more symptoms of heart failure. Significant differences were particularly evident between the two groups in dyspnea and peripheral edema. Other symptoms of heart failure, however, were not significantly more prevalent in either group.2025-05-0