Dr. Katharina Scherschel

Scientist / Scientific Study Coordinator

Molecular biologist located in Düsseldorf – enthusiastic about neurons in the heart.

Currently working at the Division of Cardiology, Evangelisches Krankenhaus Düsseldorf. Guest scientist at the Institute for Neural and Sensory Physiology, Heinrich-Heine University Düsseldorf.

Research focus: To improve the understanding of the cardiac autonomic nervous system in order to help patients with cardiac arrhythmias.


Feel free to look me up and reach out:

Publications

Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice

International Journal of Molecular Sciences, April 2021

Scherschel K, Bräuninger H, Mölders A, Erlenhardt N, Amin E, Jungen C, Pape U, Lindner D, Chetkovich DM, Klöcker N, Meyer C

Abstract: The tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b/PEX5R) is an interaction partner and auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are key for rhythm generation in the brain and in the heart. Since TRIP8b is expressed in central neurons but not in cardiomyocytes, the TRIP8b-HCN interaction has been studied intensely in the brain, but is deemed irrelevant in the cardiac conduction system. Still, to date, TRIP8b has not been studied in the intrinsic cardiac nervous system (ICNS), a neuronal network located within epicardial fat pads. In vitro electrophysiological studies revealed that TRIP8b-deficient mouse hearts exhibit increased atrial refractory and atrioventricular nodal refractory periods, compared to hearts of wild-type littermates. Meanwhile, heart rate, sino-nodal recovery time, and ventricular refractory period did not differ between genotypes. Trip8b mRNA was detected in the ICNS by quantitative polymerase chain reaction. RNAscope in situ hybridization confirmed Trip8b localization in neuronal somata and nerve fibers. Additionally, we found a very low amount of mRNAs in the sinus node and atrioventricular node, most likely attributable to the delicate fibers innervating the conduction system. In contrast, TRIP8b protein was not detectable. Our data suggest that TRIP8b in the ICNS may play a role in the modulation of atrial electrophysiology beyond HCN-mediated sino-nodal control of the heart.


Location, Dissection, and Analysis of the Murine Stellate Ganglion

JoVE Journal, December 2020

Scherschel K, Bräuninger H, Glufke K, Jungen C, Klöcker N, Meyer C

Abstract: The autonomic nervous system is a substantial driver of cardiac electrophysiology. Especially the role of its sympathetic branch is an ongoing matter of investigation in the pathophysiology of ventricular arrhythmias (VA). Neurons in the stellate ganglia (SG) – bilateral star-shaped structures of the sympathetic chain – are an important component of the sympathetic infrastructure. The SG are a recognized target for treatment via cardiac sympathetic denervation in patients with therapy-refractory VA. While neuronal remodeling and glial activation in the SG have been described in patients with VA, the underlying cellular and molecular processes that potentially precede the onset of arrhythmia are only insufficiently understood and should be elucidated to improve autonomic modulation. Mouse models allow us to study sympathetic neuronal remodeling, but identification of the murine SG is challenging for the inexperienced investigator. Thus, in-depth cellular and molecular biological studies of the murine SG are lacking for many common cardiac diseases. Here, we describe a basic repertoire for dissecting and studying the SG in adult mice for analyses at RNA level (RNA isolation for gene expression analyses, in situ hybridization), protein level (immunofluorescent whole mount staining), and cellular level (basic morphology, cell size measurement). We present potential solutions to overcome challenges in the preparation technique, and how to improve staining via quenching of autofluorescence. This allows for the visualization of neurons as well as glial cells via established markers in order to determine cell composition and remodeling processes. The methods presented here allow characterizing the SG to gain further information on autonomic dysfunction in mice prone to VA and can be complemented by additional techniques investigating neuronal and glial components of the autonomic nervous system in the heart.


Impact of the ablation technique on release of the neuronal injury marker S100B during pulmonary vein isolation

Europace, August 2020

Scherschel K, Hedenus K, Jungen C, Münkler P, Willems S, Anwar O, Klatt N, Eickholt C, Meyer C

Abstract: S100B, a well-known damage-associated molecular pattern protein is released acutely by central and peripheral nerves and upon concomitant denervation in pulmonary vein isolation (PVI). We aimed to investigate whether the ablation technique used for PVI impacts S100B release in patients with paroxysmal atrial fibrillation (AF).


Outcome after tailored catheter ablation of atrial tachycardia using ultra-high-density mapping

Journal of Cardiovascular Electrophysiology, August 2020

Jungen C, Akbulak R, Kahle AK, Eickholt C, Schaeffer B, Scherschel K, Dinshaw L, Muenkler P, Schleberger R, Nies M, Gunawardene MA, Klatt N, Hartmann J, Merbold L, Jularic M, Willems S, Meyer C

Abstract: Tailored catheter ablation of atrial tachycardias (ATs) is increasingly recommended as a potentially easy treatment strategy in the era of high-density mapping (HDM). As follow-up data are sparse, we here report outcomes after HDM-guided ablation of ATs in patients with prior catheter ablation or cardiac surgery.


Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases

JAMA Cardiology, July 2020

Lindner D, Fitzek A, Bräuninger H, Aleshcheva G, Edler C, Meissner K, Scherschel K, Kirchhof P, Escher F, Schultheiss HP, Blankenberg S, Püschel K, Westermann D

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown. Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per μg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field. In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement.


Contemporary analysis of phrenic nerve injuries following cryoballoon-based pulmonary vein isolation: A single-centre experience with the systematic use of compound motor action potential monitoring

PLOS One, June 2020

Anwar O, Gunawardene MA, Dickow J, Scherschel K, Jungen C, Münkler P, Eickholt C, Willems S, Gessler N, Meyer C

Abstract: Phrenic nerve injury (PNI) remains one of the most frequent complications during cryoballoon-based pulmonary vein isolation (CB-PVI). Since its introduction in 2013, the use of compound motor action potential (CMAP) for the prevention of PNI during CB-PVI is increasing; however, systematic outcome data are sparse. The CMAP technique was applied in conjunction with abdominal palpation during pacing manoeuvres (10 mV, 2 ms) from the superior vena cava for 388 consecutive patients undergoing CB-PVI between January 2015 and May 2017 at our tertiary arrhythmia centre. Cryoablation was immediately terminated when CMAP amplitude was reduced by 30%. Reductions in CMAP amplitude were observed in 16 (4%) of 388 patients during isolation of the right veins. Of these, 11 (69%) patients did not manifest a reduction in diaphragmatic excursions. The drop in CMAP amplitude was observed in 10 (63%) patients during ablation of the right superior pulmonary veins (PVs) and in 7 (44%) patients during ablation of the right inferior PVs. Postprocedural persistent PNI was observed in three of four patients for a duration of 6 months, with one of these patients remaining symptomatic at the 24-month follow-up. One of the four patients was lost to long-term follow-up. All PNIs occurred during right-sided CB-PVI and were preceded by a reduction in CMAP amplitude. Thus, the standardized use of CMAP surveillance during CB-PVI is easily applicable, reliable and compared with other studies, results in a lower number of PNIs.


Rationale and Design of the Hamburg City Health Study

European Journal of Epidemiology, November 2019

Jagodzinski A, Johansen C, Koch-Gromus U, Aarabi G, Adam G, Anders S, Augustin M, der Kellen RB, Beikler T, Behrendt CA, Betz CS, Bokemeyer C, Borof K, Briken P, Busch CJ, Büchel C, Brassen S, Debus ES, Eggers L, Fiehler J, Gallinat J, Gellißen S, Gerloff C, Girdauskas E, Gosau M, Graefen M, Härter M, Harth V, Heidemann C, Heydecke G, Huber TB, Hussein Y, Kampf MO, von dem Knesebeck O, Konnopka A, König HH, Kromer R, Kubisch C, Kühn S, Loges S, Löwe B, Lund G, Meyer C, Nagel L, Nienhaus A, Pantel K, Petersen E, Püschel K, Reichenspurner H, Sauter G, Scherer M, Scherschel K, Schiffner U, Schnabel RB, Schulz H, Smeets R, Sokalskis V, Spitzer MS, Terschüren C, Thederan I, Thoma T, Thomalla G, Waschki B, Wegscheider K, Wenzel JP, Wiese S, Zyriax BC, Zeller T, Blankenberg S

Abstract: The Hamburg City Health Study (HCHS) is a large, prospective, long-term, population-based cohort study and a unique research platform and network to obtain substantial knowledge about several important risk and prognostic factors in major chronic diseases. A random sample of 45,000 participants between 45 and 74 years of age from the general population of Hamburg, Germany, are taking part in an extensive baseline assessment at one dedicated study center. Participants undergo 13 validated and 5 novel examinations primarily targeting major organ system function and structures including extensive imaging examinations. The protocol includes validate self-reports via questionnaires regarding lifestyle and environmental conditions, dietary habits, physical condition and activity, sexual dysfunction, professional life, psychosocial context and burden, quality of life, digital media use, occupational, medical and family history as well as healthcare utilization. The assessment is completed by genomic and proteomic characterization. Beyond the identification of classical risk factors for major chronic diseases and survivorship, the core intention is to gather valid prevalence and incidence, and to develop complex models predicting health outcomes based on a multitude of examination data, imaging, biomarker, psychosocial and behavioral assessments. Participants at risk for coronary artery disease, atrial fibrillation, heart failure, stroke and dementia are invited for a visit to conduct an additional MRI examination of either heart or brain. Endpoint assessment of the overall sample will be completed through repeated follow-up examinations and surveys as well as related individual routine data from involved health and pension insurances. The study is targeting the complex relationship between biologic and psychosocial risk and resilience factors, chronic disease, health care use, survivorship and health as well as favorable and bad prognosis within a unique, large-scale long-term assessment with the perspective of further examinations after 6 years in a representative European metropolitan population.


Advanced mapping strategies for ablation therapy in adults with congenital heart disease

Cardiovascular Diagnosis and Therapy, October 2019

Alken FA, Klatt N, Muenkler P, Scherschel K, Jungen C, Akbulak RO, Kahle AK, Gunawardene M, Jularic M, Dinshaw L, Hartmann J, Eickholt C, Willems S, Stute F, Mueller G, Blankenberg S, Rickers C, Sinning C, Zengin-Sahm E, Meyer C

Abstract: Ultra-high density mapping (HDM) is a promising tool in the treatment of patients with complex arrhythmias. In adults with congenital heart disease (CHD), rhythm disorders are among the most common complications but catheter ablation can be challenging due to heterogenous anatomy and complex arrhythmogenic substrates. Here, we describe our initial experience using HDM in conjunction with novel automated annotation algorithms in patients with moderate to great CHD complexity. Our findings suggest that HDM in conjunction with novel automated annotation algorithms provides detailed insights into arrhythmia mechanisms and might facilitate tailored catheter ablation in patients with moderate to great CHD complexity.


Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation

American Journal of Physiology - Heart and Circulatory Physiology, October 2019

Jungen C, Scherschel K, Flenner F, Jee H, Rajendran PS, De Jong KA, Nikolaev VO, Meyer C, Ardell JL, Tompkins JD

Abstract: Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Since the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Methods and results: Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In-vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice and the kinetics of pacing-induced Ca2+ transients, recorded from isolated cardiomyocytes, were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.


EAT: What role does the fat around the heart play?

International Journal of Cardiology, August 2019

Katharina Scherschel, Nils Gosau

Abstract: Obesity is on the rise, and with it, fatty heart tissue as well. Epicardial adipose tissue (EAT) and its relationship to cardiovascular disease have been attracting more attention over the last decade. EAT is a depot of fat surrounding the heart within the pericardial sack; located predominantly around coronary arteries and the atrioventricular groove as well as at distinct positions surrounding the atria. It is thus divided into peri-ventricular and peri-atrial EAT. The latter, or more specifically, left atrial adipose tissue (LAAT) is the focus of Lopez-Canoa and colleagues in the current issue of the International Journal of Cardiology.


Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation

Science Translational Medicine, May 2019

Scherschel K*, Hedenus K*, Jungen C, Lemoine MD, Rübsamen N, Veldkamp MW, Klatt N, Lindner D, Westermann D, Casini S, Kuklik P, Eickholt C, Klöcker N, Shivkumar K, Christ T, Zeller T, Willems S, Meyer C

Abstract: Atrial fibrillation (AF), the most common sustained heart rhythm disorder worldwide, is linked to dysfunction of the intrinsic cardiac autonomic nervous system (ICNS). The role of ICNS damage occurring during catheter-based treatment of AF, which is the therapy of choice for many patients, remains controversial. We show here that the neuronal injury marker S100B is expressed in cardiac glia throughout the ICNS and is released specifically upon catheter ablation of AF. Patients with higher S100B release were more likely to be AF free during follow-up. Subsequent in vitro studies revealed that murine intracardiac neurons react to S100B with diminished action potential firing and increased neurite growth. This suggests that release of S100B from cardiac glia upon catheter-based treatment of AF is a hallmark of acute neural damage that contributes to nerve sprouting and can be used to assess ICNS damage.


Respiratory sinus arrhythmia is reduced after pulmonary vein isolation in patients with paroxysmal atrial fibrillation

Archives of Medical Science, March 2019

Christiane Jungen, Fares-Alexander Alken, Christian Eickholt, Katharina Scherschel, Pawel Kuklik, Niklas Klatt, Jana Schwarzl, Julia Moser, Mario Jularic, Ruken Oezge Akbulak, Benjamin Schaeffer, Stephan Willems, Christian Meyer

Abstract: Respiratory sinus arrhythmia (RSA) describes heart rate (HR) changes in synchrony with respiration. It is relevant for exercise capacity and mechanistically linked with the cardiac autonomic nervous system. After pulmonary vein isolation (PVI), the current therapy of choice for patients with paroxysmal atrial fibrillation (AF), the cardiac vagal tone is often diminished. We hypothesized that RSA is modulated by PVI in patients with paroxysmal AF.


Dissecting hiPSC-CM pacemaker function in a cardiac organoid model

Biomaterials, March 2019

Schulze ML, Lemoine MD, Fischer AW, Scherschel K, David R, Riecken K, Hansen A, Eschenhagen T, Ulmer BM

Abstract: Biological pacemakers could be a promising alternative to electronic pacemakers and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) may represent a suitable source for implantable cells. To further unravel this potential a thorough understanding of pacemaker function with regard to coupling processes both in the physiological and in the graft-host context is required. Here we developed a 2-component cardiac organoid model with a hiPSC-CM embryoid body (EB) as trigger casted into a rat engineered heart tissue (EHT) as arrhythmic beating substrate. Contractility recordings revealed that the EB controlled the beating activity of the EHT, leading to a regular hiPSC-CM-like beating pattern instead of the irregular beating typically seen in rat EHT. Connectivity was observed with action potential (AP) measurements and calcium transients transmitting from the EB directly into the rat EHT. Immunohistochemistry and genetically labeled hiPSC-CMs demonstrated that EB-derived and rat cells intermingled and formed a transitional zone. Connexin 43 expression followed the same pattern as histological and computer models have indicated for the human sinoatrial node. In conclusion, hiPSC-CM EBs function as a biological pacemaker in a 2-component cardiac organoid model, which provides the possibility to study electrophysiological and structural coupling mechanisms underlying propagation of pacemaker activity.


Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts

Biomolecules, January 2019

Voss S, Krüger S, Scherschel K, Warnke S, Schwarzl M, Schrage B, Girdauskas E, Meyer C, Blankenberg S, Westermann D, Lindner D

Abstract: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto /paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.


Rat atrial engineered heart tissue: a new in vitro model to study atrial biology

Basic Research in Cardiology, September 2018

Krause J, Löser A, Lemoine MD, Christ T, Scherschel K, Meyer C, Blankenberg S, Zeller T, Eschenhagen T, Stenzig J

Abstract: Engineered heart tissue (EHT) from rat cells is a useful tool to study ventricular biology and cardiac drug safety. Since atrial and ventricular cells differ significantly, EHT and other 3D cell culture formats generated from ventricular cells have been of limited value to study atrial biology. To date, reliable in vitro models that reflect atrial physiology are lacking. Therefore, we established a novel EHT model using rat atrial cells (atrial EHT, aEHT) to assess atrial physiology, contractility and drug response. The tissue constructs were characterized with regard to gene expression, histology, electrophysiology, and the response to atrial-specific drugs. We observed typical functional properties of atrial tissue in our model such as more regular spontaneous beating with lower force, shorter action potential duration, and faster contraction and relaxation compared to ventricular EHT (vEHT). The expression of atrial-specific genes and proteins was high, whereas ventricle-specific transcripts were virtually absent. The atrial-selective drug carbachol had a strong negative inotropic and chronotropic effect on aEHT only. Taken together, the results demonstrate the feasibility of aEHT as a novel atrial 3D model and as a benchmark for tissue engineering with human induced pluripotent stem cell-derived atrial-like cardiomyocytes. Atrial EHT faithfully recapitulates atrial physiology and shall be useful to study atrial molecular physiology in health and disease as well as drug response.


Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction

Proceedings of the National Academy of Sciences of the United States of America, September 2018

Hinrichs S, Scherschel K, Krüger S, Neumann JT, Schwarzl M, Yan I, Warnke S, Ojeda FM, Zeller T, Karakas M, Keller T, Meyer C, Blankenberg S, Westermann D, Lindner D

Abstract: Increased adrenomedullin (ADM) levels are associated with various cardiac diseases such as myocardial infarction (MI). ADM is cleaved off from the full-length precursor protein proadrenomedullin (ProADM) during its posttranslational processing. To date, no biological effect of ProADM is reported, while ADM infusion leads to antiapoptotic effects and improved cardiac function. Using an MI mouse model, we found an induction of ProADM gene as well as protein expression during the early phase of MI. This was accompanied by apoptosis and increasing inflammation, which substantially influence the post-MI remodeling processes. Simulating ischemia in vitro, we demonstrate that ProADM expression was increased in cardiomyocytes and cardiac fibroblasts. Subsequently, we treated ischemic cardiomyocytes with either ProADM or ADM and found that both proteins increased survival. This effect was diminishable by blocking the ADM1 receptor. To investigate whether ProADM and ADM play a role in the regulation of cardiac inflammation, we analyzed chemokine expression after treatment of cells with both proteins. While ProADM induced an expression of proinflammatory cytokines, thus promoting inflammation, ADM reduced chemokine expression. On leukocytes, both proteins repressed chemokine expression, revealing antiinflammatory effects. However, ProADM but not ADM dampened concurrent activation of leukocytes. Our data show that the full-length precursor ProADM is biologically active by reducing apoptosis to a similar extent as ADM. We further assume that ProADM induces local inflammation in affected cardiac tissue but attenuates exaggerated inflammation, whereas ADM has low impact. Our data suggest that both proteins are beneficial during MI by influencing apoptosis and inflammation.


Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System

Journal of Visualized Experiments, May 2018

Jungen C, Scherschel K, Bork NI, Kuklik P, Eickholt C, Kniep H, Klatt N, Willems S, Nikolaev VO, Meyer C

Abstract: Since its invention in the late 19th century, the Langendorff ex vivo heart perfusion system continues to be a relevant tool for studying a broad spectrum of physiological, biochemical, morphological, and pharmacological parameters in centrally denervated hearts. Here, we describe a setup for the modulation of the intracardiac autonomic nervous system and the assessment of its influence on basic electrophysiology, arrhythmogenesis, and cyclic adenosine monophosphate (cAMP) dynamics. The intracardiac autonomic nervous system is modulated by the mechanical dissection of atrial fat pads-in which murine ganglia are located mainly-or by the usage of global as well as targeted pharmacological interventions. An octapolar electrophysiological catheter is introduced into the right atrium and the right ventricle, and epicardial-placed multi-electrode arrays (MEA) for high-resolution mapping are used to determine cardiac electrophysiology and arrhythmogenesis. Förster resonance energy transfer (FRET) imaging is performed for the real-time monitoring of cAMP levels in different cardiac regions. Neuromorphology is studied by means of antibody-based staining of whole hearts using neuronal markers to guide the identification and modulation of specific targets of the intracardiac autonomic nervous system in the performed studies. The ex vivo Langendorff setup allows for a high number of reproducible experiments in a short time. Nevertheless, the partly open nature of the setup (e.g., during MEA measurements) makes constant temperature control difficult and should be kept to a minimum. This described method makes it possible to analyze and modulate the intracardiac autonomic nervous system in decentralized hearts.


Ventricular tachycardia in ischemic heart disease: the sympathetic heart and its scars

American Journal of Physiology - Heart and Circulatory Physiology, March 2017

Meyer C, Scherschel K


Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias

Nature Communications, January 2017

Jungen C, Scherschel K, Eickholt C, Kuklik P, Klatt N, Bork N, Salzbrunn T, Alken F, Angendohr S, Klene C, Mester J, Klöcker N, Veldkamp MW, Schumacher U, Willems S, Nikolaev VO, Meyer C

Abstract: The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.


Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model

Physiological Reports, September 2016

Klatt N*, Scherschel K*, Schad C, Lau D, Reitmeier A, Kuklik P, Muellerleile K, Yamamura J, Zeller T, Steven D, Baldus S, Schäffer B, Jungen C, Eickholt C, Wassilew K, Schwedhelm E, Willems S, Meyer C

Abstract: Hypertension is a major risk factor for many cardiovascular diseases and leads to subsequent concomitant pathologies such as left ventricular hypertrophy (LVH). Translational approaches using large animals get more important as they allow the use of standard clinical procedures in an experimental setting. Therefore, the aim of this study was to establish a minimally invasive ovine hypertension model using chronic angiotensin II (ANG II) treatment and to characterize its effects on cardiac remodeling after 8 weeks. Sheep were implanted with osmotic minipumps filled with either vehicle control (n = 7) or ANG II (n = 9) for 8 weeks. Mean arterial blood pressure in the ANG II-treated group increased from 87.4 ± 5.3 to 111.8 ± 6.9 mmHg (P = 0.00013). Cardiovascular magnetic resonance imaging showed an increase in left ventricular mass from 112 ± 12.6 g to 131 ± 18.7 g after 7 weeks (P = 0.0017). This was confirmed by postmortem measurement of left ventricular wall thickness which was higher in ANG II-treated animals compared to the control group (18 ± 4 mm vs. 13 ± 2 mm, respectively, P = 0.002). However, ANG II-treated sheep did not reveal any signs of fibrosis or inflammatory infiltrates as defined by picrosirius red and H&E staining on myocardial full thickness paraffin sections of both atria and ventricles. Measurements of plasma high-sensitivity C-reactive protein and urinary 8-iso-prostaglandin F2α were inconspicuous in all animals. Furthermore, multielectrode surface mapping of the heart did not show any differences in epicardial conduction velocity and heterogeneity. These data demonstrate that chronic ANG II treatment using osmotic minipumps presents a reliable, minimally invasive approach to establish hypertension and nonfibrotic LVH in sheep.


Accumulation of free oligosaccharides and tissue damage in cytosolic α-mannosidase (Man2c1)-deficient mice

Journal of Biological Chemistry, April 2014

Paciotti S, Persichetti E, Klein K, Tasegian A, Duvet S, Hartmann D, Gieselmann V, Beccari T

Abstract: Free Man(7-9)GlcNAc2 is released during the biosynthesis pathway of N-linked glycans or from misfolded glycoproteins during the endoplasmic reticulum-associated degradation process and are reduced to Man5GlcNAc in the cytosol. In this form, free oligosaccharides can be transferred into the lysosomes to be degraded completely. α-Mannosidase (MAN2C1) is the enzyme responsible for the partial demannosylation occurring in the cytosol. It has been demonstrated that the inhibition of MAN2C1 expression induces accumulation of Man(8-9)GlcNAc oligosaccharides and apoptosis in vitro. We investigated the consequences caused by the lack of cytosolic α-mannosidase activity in vivo by the generation of Man2c1-deficient mice. Increased amounts of Man(8-9)GlcNAc oligosaccharides were recognized in all analyzed KO tissues. Histological analysis of the CNS revealed neuronal and glial degeneration with formation of multiple vacuoles in deep neocortical layers and major telencephalic white matter tracts. Enterocytes of the small intestine accumulate mannose-containing saccharides and glycogen particles in their apical cytoplasm as well as large clear vacuoles in retronuclear position. Liver tissue is characterized by groups of hepatocytes with increased content of mannosyl compounds and glycogen, some of them undergoing degeneration by hydropic swelling. In addition, lectin screening showed the presence of mannose-containing saccharides in the epithelium of proximal kidney tubules, whereas scattered glomeruli appeared collapsed or featured signs of fibrosis along Bowman’s capsule. Except for a moderate enrichment of mannosyl compounds and glycogen, heterozygous mice were normal, arguing against possible toxic effects of truncated Man2c1. These findings confirm the key role played by Man2c1 in the catabolism of free oligosaccharides.


Hepatoma-derived growth factor and nucleolin exist in the same ribonucleoprotein complex

BMC Biochemistry, January 2013

Bremer S, Klein K, Sedlmaier A, Abouzied M, Gieselmann V, Franken S

Abstract: BACKGROUND: Hepatoma-derived growth factor (HDGF) is a protein which is highly expressed in a variety of tumours. HDGF has mitogenic, angiogenic, neurotrophic and antiapoptotic activity but the molecular mechanisms by which it exerts these activities are largely unknown nor has its biological function in tumours been elucidated. Mass spectrometry was performed to analyse the HDGFStrep-tag interactome. By Pull-down-experiments using different protein and nucleic acid constructs the interaction of HDGF and nucleolin was investigated further. RESULTS: A number of HDGFStrep-tag copurifying proteins were identified which interact with RNA or are involved in the cellular DNA repair machinery. The most abundant protein, however, copurifying with HDGF in this approach was nucleolin. Therefore we focus on the characterization of the interaction of HDGF and nucleolin in this study. We show that expression of a cytosolic variant of HDGF causes a redistribution of nucleolin into the cytoplasm. Furthermore, formation of HDGF/nucleolin complexes depends on bcl-2 mRNA. Overexpression of full length bcl-2 mRNA increases the number of HDGF/nucleolin complexes whereas expression of only the bcl-2 coding sequence abolishes interaction completely. Further examination reveals that the coding sequence of bcl-2 mRNA together with either the 5’ or 3’ UTR is sufficient for formation of HDGF/nucleolin complexes. When bcl-2 coding sequence within the full length cDNA is replaced by a sequence coding for secretory alkaline phosphatase complex formation is not enhanced. CONCLUSION:The results provide evidence for the existence of HDGF and nucleolin containing nucleoprotein complexes which formation depends on the presence of specific mRNAs. The nature of these RNAs and other components of the complexes should be investigated in future.


Lysosomal di-N-acetylchitobiase-deficient mouse tissues accumulate Man2GlcNAc2 and Man3GlcNAc2

Biochimica et Biophysica Acta, July 2012

Persichetti E, Klein K, Paciotti S, Lecointe K, Balducci C, Franken S, Duvet S, Matzner U, Roberti R, Hartmann D, Gieselmann V, Beccari T

Abstract: Most lysosomal storage diseases are caused by defects in genes encoding for acidic hydrolases. Deficiency of an enzyme involved in the catabolic pathway of N-linked glycans leads to the accumulation of the respective substrate and consequently to the onset of a specific storage disorder. Di-N-acetylchitobiase and core specific α1-6mannosidase represent the only exception. In fact, to date no lysosomal disease has been correlated to the deficiency of these enzymes. We generated di-N-acetylchitobiase-deficient mice by gene targeting of the Ctbs gene in murine embryonic stem cells. Accumulation of Man2GlcNAc2 and Man3GlcNAc2 was evaluated in all analyzed tissues and the tetrasaccharide was detected in urines. Multilamellar inclusion bodies reminiscent of polar lipids were present in epithelia of a scattered subset of proximal tubules in the kidney. Less constantly, enlarged Kupffer cells were observed in liver, filled with phagocytic material resembling partly digested red blood cells. These findings confirm an important role for lysosomal di-N-acetylchitobiase in glycans degradation and suggest that its deficiency could be the cause of a not yet described lysosomal storage disease.


* These authors contributed equally.

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Visualisation of the “Brain within the Heart”

This animation shows the nervous system of a mouse heart – which also exists in the human heart. Stained in green are parasympathetic neurons and nerves, stained in red are sympathetic neurons and nerves.

Together, these two branches of the autonomic nervous system modulate our heart rhythm beat-to-beat. This remarkable network allows our body to adapt to environmental changes – be it an immediate danger (fight or flight) – or relaxation (rest and digest).

Curriculum Vitae

Katharina Scherschel, née Klein

 

Academic Career

Since 12/2020:
Guest scientist at the Institute for Neural and Sensory Physiology, Heinrich-Heine University Düsseldorf

Since 04/2020:
Scientific Study Coordinator, Division of Cardiology, Evangelisches Krankenhaus Düsseldorf

04/2014 - 09/2020
Postdoc, Department for Cardiology-Electrophysiology at the University Heart & Vascular Center Hamburg

11/2008 – 02/2013:
Doctoral thesis, Biology, Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn

10/2007 – 09/2008:
Diploma thesis, Biology, Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn

10/2004 – 04/2006:
Diploma (Diplom), Rheinische Friedrich-Willhelms-Universität Bonn

10/2002 – 09/2004:
Intermediate diploma (Vordiplom), Heinrich-Heine Universität Düsseldorf

09/1993 – 07/2002:
A-levels (Abitur), Kopernikus-Gymnasium Duisburg-Walsum

Reviewer for

Membership

 

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