[{"content":"Abstract This case-control study examines associations of coronary microvascular dysfunction (CMD) with occurrence of premature ventricular contractions among patients with stable angina or equivalent symptoms.\nPermalink\rhttps://doi.org/10.1001/jamanetworkopen.2025.46595\nhttps://pubmed.ncbi.nlm.nih.gov/41335442\nCite this article:\nKahle AK, Wafaisade B, Alken FA, Scherschel K, Zhu E, Cicco NA, Bejinariu AG, Bönner F, Kelm M, Cramer M, Meyer C. Coronary Microvascular Dysfunction and Premature Ventricular Contractions in Patients With Stable Angina. JAMA Netw Open. 2025 Dec 1;8(12):e2546595. doi: 10.1001/jamanetworkopen.2025.46595. PMID: 41335442; PMCID: PMC12676358.\n","permalink":"https://scherschel.science/publications/2025-12-01-jama-netw-open/","summary":"JAMA Network Open","title":"Coronary Microvascular Dysfunction and Premature Ventricular Contractions in Patients With Stable Angina"},{"content":"Abstract Insulin-like growth factor 1 (IGF-1) controls cardiac growth, metabolism, and contractility. Whereas IGF-1 deficiency is associated with cardiovascular risk, the activation of its signal transduction may be cardioprotective after acute myocardial infarction. Clinical studies evaluate the therapeutic potential of systemic IGF-1 in disease conditions including heart failure, and reported tachycardia as a common side effect. Here, we demonstrate that IGF-1 accelerates cardiac pacemaking in an ex vivo mouse sinoatrial node preparation read out by optical voltage mapping. Heterologous reconstitution experiments in Xenopus laevis oocytes combining extracellular epitope tagging and electrophysiology reveal an increase in cell surface expression of the main cardiac pacemaker channel isoform HCN4 by IGF-1, which stimulates the Rab11-dependent endosomal recycling of the channel protein. In summary, the study not only adds to the modes of HCN channel regulation by growth factor signaling, but may also extend our understanding of arrhythmogenesis, commonly observed in consequence of IGF-1 dysregulation including cardiac hypertrophy.\nPermalink\rhttps://doi.org/10.1016/j.yjmcc.2025.10.015\nhttps://pubmed.ncbi.nlm.nih.gov/41177447\nCite this article:\nErlenhardt N, Wohlfarth F, Moussavi-Torshizi SE, Koch A, Strasdeit T, Scherschel K, Amin E, Anstötz M, Meyer C, Klöcker N. IGF-1 promotes cell surface expression of HCN4 pacemaker channels contributing to tachycardia. J Mol Cell Cardiol. 2026 Jan;210:165-174. doi: 10.1016/j.yjmcc.2025.10.015. Epub 2025 Nov 1. PMID: 41177447.\n","permalink":"https://scherschel.science/publications/2025-11-01-j-mol-cell-cardiol/","summary":"Journal of Molecular and Cellular Cardiology","title":"IGF-1 promotes cell surface expression of HCN4 pacemaker channels contributing to tachycardia"},{"content":"Abstract The heart adapts to changing physiological demands through bidirectional interactions with the brain. These are mediated via extensive feedback loops of the cardiac autonomic nervous system, a complex network of neurons and glial cells. Although the presence of glia in the heart and its nervous system has been known for decades, only recently has an understanding of their contribution to cardiac physiology and pathophysiology emerged. As new types of cardiac glia are discovered, it becomes evident that they represent heterogeneous cell populations in distinct anatomical locations of the cardiac nervous system, contributing not only to autonomic control of the healthy heart but also to pathological changes in the diseased heart.\nPermalink\rhttps://doi.org/10.1038/s41583-025-00974-7\nhttps://pubmed.ncbi.nlm.nih.gov/41107549\nCite this article:\nScherschel K, Wolf H, Ajijola OA, Shivkumar K, Lindner D, Gomez-Sanchez JA, Meyer C. Glia of the heart\u0026rsquo;s nervous system. Nat Rev Neurosci. 2025 Oct 17. doi: 10.1038/s41583-025-00974-7. Epub ahead of print. PMID: 41107549.\n","permalink":"https://scherschel.science/publications/2025-10-17-nat-rev-neurosci/","summary":"Nature Reviews Neuroscience","title":"Glia of the heart’s nervous system"},{"content":"Abstract Background Acutely effective repeated radiofrequency catheter ablation (RFCA) after previous atrial fibrillation ablation depends on several parameters including local impedance (LI), contact force (CF), and power.\nObjective We aimed to investigate the relationship of LI, CF, and power to the LI drop in a repeated atrial RFCA environment.\nMethods Consecutive patients undergoing repeated atrial RFCA were studied. High-quality local electrograms were analyzed for morphology changes indicating effective RFCA and associated LI dynamics. The influence of baseline LI, mean CF, and power on the LI drop was analyzed. Investigated power levels included ≤25 W, 30 W, and ≥40 W.\nResults A total of 1390 RFCA points from 48 patients (48% female; median age, 70 years) were analyzed. Of 309 analyzed electrograms, 40.5% showed effective RFCA morphology changes with an elevated median LI drop (effective, 19.7 Ω; partially effective, 14.1 Ω; P \u0026lt; .001). CF showed the highest correlation to the LI drop within high baseline LI and when applying ≥40 W (low baseline LI, R = 0.39; intermediate, R = 0.66; high, R = 0.72). Within low baseline LI regions, CF levels showed a lower correlation to the LI drop (≤25 W, R = 0.30; 30 W, R = 0.35; ≥40 W, R = 0.39). A mean CF ≥10 g resulted in elevated LI drops with higher power compared with lower power within all baseline LI tertiles (P \u0026lt; .001 each).\nConclusion Within high baseline LI regions, CF plays a greater role for the maximum LI drop when higher power is chosen. A mean CF ≥10 g ensures elevated LI drops with increasing power levels.\nPermalink\rhttps://doi.org/10.1016/j.hrthm.2024.09.026\nhttps://pubmed.ncbi.nlm.nih.gov/39293497\nCite this article:\nAlken FA, Scherschel K, Zhu E, Wafaisade B, Kahle AK, Meyer C. Interactions of contact force, impedance, and power during repeated atrial arrhythmia ablation after previous atrial fibrillation ablation. Heart Rhythm. 2025 Jun;22(6):1411-1420. doi: 10.1016/j.hrthm.2024.09.026. Epub 2024 Sep 16. PMID: 39293497.\n","permalink":"https://scherschel.science/publications/2025-06-22-heart-rhythm/","summary":"Heart Rhythm","title":"Interactions of contact force, impedance, and power during repeated atrial arrhythmia ablation after previous atrial fibrillation ablation"},{"content":"Abstract Aims Modulation of cardiac neural control is increasingly explored to treat cardiac arrhythmias. While the atrially located ganglionated plexus (GPs) have been studied intensively, characterization of ventricular GPs is sparse. This proof-of-principle study aimed to assess the role of the posterior descending GP (PDGP) for neural control of cardiac electrophysiology, while offering a translational roadmap into clinical practice.\nMethods and results Since an initial systematic literature review revealed the PDGP as a small, consolidated GP on the posterior left ventricle (LV) in dogs, swine, and humans, we subsequently conducted morphological C57BL/6 murine studies (n = 43) indicating ventricular GPs in only 10% of hearts. Based on our initial findings, in a proof-of-principle study analysing 4300 local unipolar electrograms from a multi-electrode sock, the impact of functional PDGP modulation was studied in an ex vivo retrograde-perfused porcine model. Wave propagation characteristics determined by epicardial activation mapping demonstrated increased dispersion of conduction velocity during high-frequency (8.52 ± 2.24 radian vs. 2.79 ± 0.89 radian; P = 0.018) and nicotine stimulation (19.79 ± 6.49 radian vs. 2.79 ± 0.89 radian; P = 0.044) compared to paced rhythm. High-frequency stimulation prolonged activation recovery intervals in the posterior (257.8 ± 6.7 ms vs. 244.8 ± 1.9 ms; P = 0.044) and basal (258.1 ± 4.2 ms vs. 244.8 ± 1.9 ms; P =0.039) right ventricle compared to the posterior LV. Analysis of explanted human hearts confirmed the presence of the PDGP within epicardial adipose tissue near its eponymous coronary artery and the posteromedial left atrial GP. Three-dimensionally reconstructed human hearts suggested the PDGP localization characterized by inter-patient anatomical variability.\nConclusion The present translational approach to ventricular innervation demonstrates first evidence of the functional relevance of the PDGP, with morphological findings indicating species-related differences. Novel imaging modalities might pave the way for future functional and therapeutic interventions.\nPermalink\rhttps://doi.org/10.1093/europace/euaf099\nhttps://pubmed.ncbi.nlm.nih.gov/40358248\nCite this article:\nKahle AK, Klatt N, Scherschel K, Jungen C, Kuklik P, Alken FA, Klöcker N, Willems S, Weber E, Boeken U, Lichtenberg A, Bernhardt A, Hakmi S, Pauza DH, Meyer C. Translational approach to ventricular innervation: the posterior descending ganglionated plexus. Europace. 2025 May 7;27(5):euaf099. doi: 10.1093/europace/euaf099. PMID: 40358248; PMCID: PMC12123069.\n","permalink":"https://scherschel.science/publications/2025-05-13-europace/","summary":"EP Europace","title":"Translational approach to ventricular innervation: the posterior descending ganglionated plexus"},{"content":"Abstract Background Age is a relevant risk factor for the development of atrial arrhythmias and an independent predictor of adverse cardiovascular outcomes. The incidence of atrial tachycardia (AT) is known to increase with aging, but so far, there are no data on elderly patients with AT. Therefore, we sought to assess the safety and outcomes of AT ablation in patients ≥75 years compared to those \u0026lt;75 years.\nMethods A total of 420 consecutive patients undergoing AT ablation after previous cardiac interventions (mean 2.1 ± 0.1 prior ablation procedures) were analyzed. Safety, as well as acute and mid-term outcomes of AT ablation were compared between 140 patients ≥75 years (mean age 78.1 ± 0.2 years, 22.9% aged ≥80 years (range 80–86 years)) and 280 patients \u0026lt;75 years (mean age 62.2 ± 0.6 years). Results: Patients ≥75 years were more often female (54.3% vs. 38.2%; p = 0.0024) and presented with more cardiac comorbidities, including arterial hypertension (85.0% vs. 64.3%; p \u0026lt; 0.0001) and coronary artery disease (33.6% vs. 18.2%; p = 0.0006). Acute success of AT ablation was reached in 96.4% vs. 97.9% of patients (p = 0.5173). Major complications (1.4% vs. 0.7%; p = 0.6035) and duration of hospital stay (2 (IQR 2–4) days vs. 2 (IQR 2–3) days; p = 0.9125) did not differ significantly between groups. During a follow-up of 364 (IQR 183–729.5) days, arrhythmia recurrences occurred in 45.0% vs. 49.3% (p = 0.4684), whereas repeat ablation was less frequently performed in patients ≥75 years (25.7% vs. 36.1%; p = 0.0361).\nConclusions AT ablation in patients ≥75 years after previous cardiac interventions in tertiary arrhythmia centers is safe and effective. Therefore, AT ablation should not be ruled out in elderly patients due to age alone, but should be considered based on arrhythmia burden, symptom severity and concomitant clinical and procedural risk factors.\nPermalink\rhttps://doi.org/10.3390/jcm14030675\nhttps://pubmed.ncbi.nlm.nih.gov/39941346\nCite this article:\nKahle AK, Alken FA, Scherschel K, Zhu E, Gunawardene MA, Metzner A, Willems S, Meyer C. Safety and Outcomes of Catheter Ablation for Consecutive Atrial Tachycardia in Elderly Patients After Previous Cardiac Interventions. J Clin Med. 2025 Jan 21;14(3):675. doi: 10.3390/jcm14030675. PMID: 39941346; PMCID: PMC11818208.\n","permalink":"https://scherschel.science/publications/2025-01-21-j-clin-med/","summary":"Journal of Clinical Medicine","title":"Safety and Outcomes of Catheter Ablation for Consecutive Atrial Tachycardia in Elderly Patients After Previous Cardiac Interventions"},{"content":"Abstract Objective and Background Data on incidence of in-hospital pulmonary embolisms (PE) after catheter ablation (CA) are scarce. To gain further insights, we sought to provide new findings through case-based analyses of administrative data.\nMethods Incidences of PE after CA of supraventricular tachycardias (SVT), atrial fibrillation (AF), atrial flutter (AFlu), and ventricular tachycardias (VT) in three German tertiary centers between 2005 and 2020 were determined and coded by the G-DRG (German Diagnosis Related Groups System) and OPS (German Operation and Procedure Classification) systems. An administrative search was performed with a consecutive case-based analysis.\nResults Overall, 47,344 ablations were analyzed (10,037 SVT; 28,048 AF; 6,252 AFlu; 3,007 VT). PE occurred in 14 (0.03%) predominantly female (n = 9; 64.3%) patients with a mean age of 55.3 ± 16.9 years, body mass index 26.2 ± 5.1 kg/m2, and left ventricular ejection fraction of 56 ± 13.6%. PE incidences were 0.05% (n = 5) for SVT, 0.02% (n = 5) for AF, and 0.13% (n = 4) for VT ablations. No patient suffered PE after AFlu ablation. Five patients (35.7%) with PE after CA had no prior indication for oral anticoagulation (OAC). Preprocedural international normalized ratio in PE patients was 1.2 ± 0.5. Most patients with PE following CA presented with symptoms the day after the procedure (n = 9) after intraprocedural heparin application of 12,943.2 ± 5,415.5 IU. PE treatment included anticoagulation with either phenprocoumon (n = 5) or non-vitamin K-dependent OAC (n = 9). Two patients with PE died after VT/AF ablation, respectively. The remaining patients were discharged without sequels.\nConclusion Over a 15-year period, incidence of PE after ablation is low, particularly low in patients with ablation for AF/AFlu. This is most likely due to stricter anticoagulation management in these patients compared with those receiving SVT/VT ablation procedures and could argue for continuation of OAC prior to ablation. Optimizing periprocedural anticoagulation management should be subject of further prospective trials.\nPermalink\rhttps://doi.org/10.1055/s-0044-1785519\nhttps://pubmed.ncbi.nlm.nih.gov/38555641\nCite this article:\nDoldi F, Geßler N, Anwar O, Kahle AK, Scherschel K, Rath B, Köbe J, Lange PS, Frommeyer G, Metzner A, Meyer C, Willems S, Kuck KH, Eckardt L. In-Hospital Pulmonary Arterial Embolism after Catheter Ablation of Over 45,000 Cardiac Arrhythmias: Individualized Case Analysis of Multicentric Data. Thromb Haemost. 2024 Sep;124(9):861-869. doi: 10.1055/s-0044-1785519. Epub 2024 Mar 31. PMID: 38555641.\n","permalink":"https://scherschel.science/publications/2024-03-31-thromb-haemost/","summary":"Thrombosis and Haemostasis","title":"In-Hospital Pulmonary Arterial Embolism after Catheter Ablation of Over 45,000 Cardiac Arrhythmias: Individualized Case Analysis of Multicentric Data"},{"content":"Abstract Aims In-hospital complications of catheter ablation for atrial fibrillation (AF), atrial flutter (AFL), and ventricular tachycardia (VT) may be overestimated by analyses of administrative data.\nMethods and results We determined the incidences of in-hospital mortality, major bleeding, and stroke around AF, AFL, and VT ablations in four German tertiary centres between 2005 and 2020. All cases were coded by the G-DRG- and OPS-systems. Uniform code search terms were applied defining both the types of ablations for AF, AFL, and VT and the occurrence of major adverse events including femoral vascular complications, iatrogenic tamponade, stroke, and in-hospital death. Importantly, all complications were individually reviewed based on patient-level source records. Overall, 43 031 ablations were analysed (30 361 AF; 9364 AFL; 3306 VT). The number of ablations/year more than doubled from 2005 (n = 1569) to 2020 (n = 3317) with 3 times and 2.5 times more AF and VT ablations in 2020 (n = 2404 and n = 301, respectively) as compared to 2005 (n = 817 and n = 120, respectively), but a rather stable number of AFL ablations (n = 554 vs. n = 612). Major peri-procedural complications occurred in 594 (1.4%) patients. Complication rates were 1.1% (n = 325) for AF, 1.0% (n = 95) for AFL, and 5.3% (n = 175) for VT. With an increase in complex AF/VT procedures, the overall complication rate significantly increased (0.76% in 2005 vs. 1.81% in 2020; P = 0.004); but remained low over time. Following patient-adjudication, all in-hospital cardiac tamponades (0.7%) and strokes (0.2%) were related to ablation. Major femoral vascular complications requiring surgical intervention occurred in 0.4% of all patients. The in-hospital mortality rate adjudicated to be ablation-related was lower than the coded mortality rate: AF: 0.03% vs. 0.04%; AFL: 0.04% vs. 0.14%; VT: 0.42% vs. 1.48%.\nConclusion Major adverse events are low and comparable after catheter ablation for AFL and AF (∼1.0%), whereas they are five times higher for VT ablations. In the presence of an increase in complex ablation procedures, a moderate but significant increase in overall complications from 2005–20 was observed. Individual case analysis demonstrated a lower than coded ablation-related in-hospital mortality. This highlights the importance of individual case adjudication when analysing administrative data.\nPermalink\rhttps://doi.org/10.1093/europace/euad361 https://pubmed.ncbi.nlm.nih.gov/38102318\nCite this article:\nEckardt L, Doldi F, Anwar O, Gessler N, Scherschel K, Kahle AK, von Falkenhausen AS, Thaler R, Wolfes J, Metzner A, Meyer C, Willems S, Köbe J, Lange PS, Frommeyer G, Kuck KH, Kääb S, Steinbeck G, Sinner MF. Major in-hospital complications after catheter ablation of cardiac arrhythmias: individual case analysis of 43 031 procedures. Europace. 2023 Dec 28;26(1):euad361. doi: 10.1093/europace/euad361. PMID: 38102318; PMCID: PMC10754182.\n","permalink":"https://scherschel.science/publications/2023-12-28-europace/","summary":"EP Europace","title":"Major in-hospital complications after catheter ablation of cardiac arrhythmias: individual case analysis of 43 031 procedures"},{"content":"Abstract Background Coronavirus disease 2019 (COVID-19) has a great impact on both, physical and psychological wellbeing. The COVID-19 pandemic promoted increasing digitalization of the work environment and social isolation. This psychosocial stress in turn can induce physical distress with clinical manifestation. So can the changed work and social environment in the COVID-19 pandemic trigger acute cardiovascular disease?\nCase description Here, we present a case of a 56-year-old postmenopausal woman suffering from Takotsubo cardiomyopathy (TTC) evoked by emotional stress during a virtual work meeting. Like many others, our patient was urged to work from home (WFH) in accordance with the contact restrictions due to COVID-19. She presented at our chest pain unit with typical angina pectoris-like symptoms such as chest pain and dyspnea. Laboratory analysis confirmed increased troponin levels and evolving T wave inversion in electrocardiogram. Acute coronary syndrome management was commenced. Coronary angiography and left ventriculography revealed non-obstructive coronary arteries and apical ballooning syndrome. Due to immediate guideline-directed treatment with bisoprolol, ramipril, spironolactone and acetylsalicylic acid the patient’s condition improved so that she could be discharged after seven days. During a 3-month follow-up the patient showed a normalized ejection fraction and reported no discomfort anymore.\nConclusions The ongoing COVID-19 pandemic has also elucidated the importance of the psychosocial health issues in acute cardiovascular care. Having in mind that the social and work environment recently has changed immensely, thus enforcing social isolation and emotional distress, doctors as well as patients must consider TTC as possible etiology of sudden chest pain.\nPermalink\rhttps://doi.org/10.21037/acr-23-18\nhttps://pubmed.ncbi.nlm.nih.gov/37942034\nCite this article:\nZhu E, Scherschel K, Schedlowski M, Meyer C. Takotsubo cardiomyopathy following a virtual work meeting during COVID-19 pandemic: a case report. AME Case Rep. 2023 Sep 15;7:40. doi: 10.21037/acr-23-18. PMID: 37942034; PMCID: PMC10628416.\n","permalink":"https://scherschel.science/publications/2023-10-30-ame-case-rep/","summary":"AME Case Reports","title":"Takotsubo cardiomyopathy following a virtual work meeting during COVID-19 pandemic: a case report"},{"content":"Long-term results of catheter ablation for AV nodal reentry tachycardias and accessory pathways\nZusammenfassung Die AV-Knoten-Reentry-Tachykardie (AVNRT) sowie AV-Reentry-Tachykardie (AVRT) bei akzessorischen Leitungsbahnen (AP) gehören zu den häufigsten supraventrikulären Tachykardien. Aktuelle Langzeitergebnisse der Katheterablation zeigen bei Kindern und Erwachsenen hohe Erfolgsraten von ca. 97 % (AVNRT) bzw. 92 % (AP). Das Risiko für schrittmacherpflichtige atrioventrikuläre (AV) Blockierungen liegt für die AVNRT bei 0,4–0,8 % bzw. für AP bei 0,1–0,2 %. Reduzierte Erfolgsraten von 87–93 % und erhöhte AV-Blockierungsraten bis zu 10 % zeigen sich bei Patient:innen mit komplexen kongenitalen Herzfehlern. Eine im Rahmen dyssynchroner Ventrikelerregung bei Präexzitation oder permanenten Reentry-Tachykardien auftretende Herzinsuffizienz zeigt nach Katheterablation eine hohe Remissionsrate von \u0026gt; 90 %. Zusammenfassend zeigt die Ablationstherapie von AVNRT und AP populationsübergreifend eine hohe Erfolgsrate bei sicherer Anwendbarkeit und stellt daher heute für die meisten Betroffenen die langfristige Therapie der ersten Wahl dar.\nAbstract Atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia in patients with accessory pathways (AP) are common supraventricular tachycardias. High long-term efficacy of about 97% (AVNRT) and 92% (AP) has been observed in children and adults. The risk of occurring atrioventricular block is low (0.4–0.8% during AVNRT, 0.1–0.2% for AP). Catheter ablation shows a lower efficacy of 87–93% and elevated atrioventricular block risk up to 10% in patient groups with complex congenital heart disease. Nonsynchronized ventricular activation during preexcitation or permanent reentrant tachycardias can induce heart failure, and remission of left ventricular function can be expected in \u0026gt; 90% after successful catheter ablation. Therefore, catheter ablation is the long-term therapy of choice for AVNRT and AP with high efficacy and safety for most patient populations.\nPermalink\rhttps://doi.org/10.1007/s00399-023-00965-0\nhttps://pubmed.ncbi.nlm.nih.gov/37861731\nCite this article:\nAlken FA, Scherschel K, Zhu E, Kahle AK, Meyer C. Langzeitergebnisse der Katheterablation bei AV-Knoten-Reentry-Tachykardien und akzessorischen Leitungsbahnen [Long-term results of catheter ablation for AV nodal reentry tachycardias and accessory pathways]. Herzschrittmacherther Elektrophysiol. 2023 Dec;34(4):278-285. German. doi: 10.1007/s00399-023-00965-0. Epub 2023 Oct 20. PMID: 37861731.\n","permalink":"https://scherschel.science/publications/2023-10-20-herzschrittmacherther/","summary":"Herzschrittmachertherapie + Elektrophysiologie","title":"Langzeitergebnisse der Katheterablation bei AV-Knoten-Reentry-Tachykardien und akzessorischen Leitungsbahnen"},{"content":"Abstract Background Atrial tachycardias (AT) occurring in patients after previous atrial fibrillation (AF) ablation are increasingly observed in clinical practice. Catheter ablation is the treatment of choice but an optimal workflow to improve patient outcome has not been defined. The purpose of this study was to assess procedural and clinical outcome depending on baseline rhythm at the beginning of AT ablation.\nMethods A total of 380 patients (69 (61–75) years, 56.6% male) who underwent catheter ablation for consecutive AT after previous AF ablation were studied.\nResults At the beginning of the procedure, 140 patients (36.8%) presented in sinus rhythm (SR), 208 (54.7%) with AT and 32 (8.4%) with AF. Patients in SR or with AT underwent shorter procedures (173 (132–213) minutes vs. 161 (120–203) minutes vs. 226 (154–249) minutes; p = 0.002) with more frequent termination to SR (87.9% vs. 81.3% vs. 56.3%; p \u0026lt; 0.001) than patients with AF. Acute procedural success did not differ between patients in SR or with AT but was higher compared to those with AF (96.4% vs. 97.1% vs. 87.5%; p = 0.033). During a follow-up of 290 (181–680) days, patients in baseline SR experienced arrhythmia recurrences less often (36.4% vs. 49.5% vs. 68.8%; p = 0.002) than patients with AT or AF.\nConclusion Baseline rhythm during AT ablation predicts procedural and clinical outcome. Whereas acute procedural success does not differ between patients in SR or with AT, patients presenting in SR have a more favorable mid-term success rate.\nPermalink\rhttps://doi.org/10.1007/s00392-023-02292-3\nhttps://pubmed.ncbi.nlm.nih.gov/37710016\nCite this article:\nKahle AK, Alken FA, Scherschel K, Meyer C. Prognostic implications of baseline rhythm during catheter ablation for atrial tachycardia. Clin Res Cardiol. 2025 Jan;114(1):53-63. doi: 10.1007/s00392-023-02292-3. Epub 2023 Sep 15. PMID: 37710016.\n","permalink":"https://scherschel.science/publications/2023-09-15-clin-res-cardiol/","summary":"Clinical Research in Cardiology","title":"Prognostic implications of baseline rhythm during catheter ablation for atrial tachycardia"},{"content":"Editor’s summary Changes in innervation of the heart can contribute to arrhythmias, and the risk of arrhythmias greatly increases with age. Wagner et al. uncovered a mechanism connecting these two phenomena. The authors studied young and aging mice and demonstrated that innervation of the heart decreases with age. Age-related accumulation of senescent cells promotes the release of semaphorin-3A, which reduces the density of neuronal axons in the heart. At the same time, aging is associated with a decrease in a microRNA that counteracts the effects of semaphorin-3A, further tipping the balance toward decreased innervation. These age-related losses in innervation could be reversed by treating the mice with senolytic drugs, suggesting a potential therapeutic approach.\n—Yevgeniya Nusinovich\nAbstract Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes. Aging down-regulates microRNA 145 (miR-145) and derepresses the neurorepulsive factor semaphorin-3A. miR-145 deletion, which increased Sema3a expression or endothelial Sema3a overexpression, reduced axon density, mimicking the aged-heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reversed Sema3a expression, preserved heart rate patterns, and reduced electrical instability. These data suggest that senescence-mediated regulation of nerve density contributes to age-associated cardiac dysfunction.\nPermalink\rhttps://doi.org/10.1126/science.ade4961\nhttps://pubmed.ncbi.nlm.nih.gov/37616346\nCite this article:\nWagner JUG, Tombor LS, Malacarne PF, Kettenhausen LM, Panthel J, Kujundzic H, Manickam N, Schmitz K, Cipca M, Stilz KA, Fischer A, Muhly-Reinholz M, Abplanalp WT, John D, Mohanta SK, Weber C, Habenicht AJR, Buchmann GK, Angendohr S, Amin E, Scherschel K, Klöcker N, Kelm M, Schüttler D, Clauss S, Günther S, Boettger T, Braun T, Bär C, Pham MD, Krishnan J, Hille S, Müller OJ, Bozoglu T, Kupatt C, Nardini E, Osmanagic-Myers S, Meyer C, Zeiher AM, Brandes RP, Luxán G, Dimmeler S. Aging impairs the neurovascular interface in the heart. Science. 2023 Aug 25;381(6660):897-906. doi: 10.1126/science.ade4961. Epub 2023 Aug 24. PMID: 37616346.\n","permalink":"https://scherschel.science/publications/2023-08-25-science/","summary":"Science","title":"Aging impairs the neurovascular interface in the heart"},{"content":"\rPermalink\rhttps://doi.org/10.1161/circep.122.011598\nhttps://pubmed.ncbi.nlm.nih.gov/36938715\nCite this article:\nLemoine MD, Mencke C, Nies M, Obergassel J, Scherschel K, Wieboldt H, Schleberger R, My I, Rottner L, Moser J, Kany S, Wenzel JP, Moser F, Dinshaw L, Münkler P, Reissmann B, Ouyang F, Meyer C, Blankenberg S, Zeller T, Fabritz L, Rillig A, Metzner A, Kirchhof P. Pulmonary Vein Isolation by Pulsed-field Ablation Induces Less Neurocardiac Damage Than Cryoballoon Ablation. Circ Arrhythm Electrophysiol. 2023 Apr;16(4):e011598. doi: 10.1161/CIRCEP.122.011598. Epub 2023 Mar 20. PMID: 36938715.\n","permalink":"https://scherschel.science/publications/2023-04-16-circ-arrhythm-electrophysiol/","summary":"Circulation: Arrhythmia and Electrophysiology","title":"Pulmonary Vein Isolation by Pulsed-field Ablation Induces Less Neurocardiac Damage Than Cryoballoon Ablation"},{"content":"Abstract Aims Cardiac arrhythmia originating from the papillary muscle (PM) can trigger ventricular fibrillation (VF) and cause sudden cardiac death even in the absence of structural heart disease. Most premature ventricular contractions, however, are benign and hitherto difficult to distinguish from a potentially fatal arrhythmia. Altered repolarization characteristics are associated with electrical instability, but electrophysiological changes which precede degeneration into VF are still not fully understood.\nMethods and results Ventricular arrhythmia (VA) was induced by aconitine injection into PMs of healthy sheep. To investigate mechanisms of degeneration of stable VA into VF in structurally healthy hearts, endocardial high-density and epicardial mapping was performed during sinus rhythm (SR) and VA. The electrical restitution curve, modelling the relation of diastolic interval and activation recovery interval (a surrogate parameter for action potential duration), is steeper in VA than in non-arrhythmia (ventricular pacing and SR). Steeper restitution curves reflect electrical instability and propensity to degenerate into VF. Importantly, we find the parameter repolarization time in relation to cycle length (RT/CL) to differentiate self-limiting from degenerating arrhythmia with high specificity and sensitivity.\nConclusion RT/CL may serve as a simple index to aid differentiation between self-limiting and electrically instable arrhythmia with the propensity to degenerate to VF. RT/CL is independent of cycle length and could easily be measured to identify electrical instability in patients.\nPermalink\rhttps://doi.org/10.1093/europace/euac126\nhttps://pubmed.ncbi.nlm.nih.gov/35989424\nCite this article:\nMünkler P, Klatt N, Scherschel K, Kuklik P, Jungen C, Cavus E, Eickholt C, Christoph J, Lemoine MD, Christ T, Willems S, Riedel R, Kirchhof P, Meyer C. Repolarization indicates electrical instability in ventricular arrhythmia originating from papillary muscle. Europace. 2023 Feb 16;25(2):688-697. doi: 10.1093/europace/euac126. PMID: 35989424; PMCID: PMC9935011.\n","permalink":"https://scherschel.science/publications/2023-02-16-europace/","summary":"EP Europace","title":"Repolarization indicates electrical instability in ventricular arrhythmia originating from papillary muscle"},{"content":"Abstract Aims The incidence of in-hospital post-interventional complications and mortality after ablation of supraventricular tachycardia (SVT) vary among the type of procedure and most likely the experience of the centre. As ablation therapy of SVT is progressively being established as first-line therapy, further assessment of post-procedural complication rates is crucial for health care quality.\nMethods and results We aimed at determining the incidence of in-hospital mortality and bleeding complications from SVT ablations in German high-volume electrophysiological centres between 2005 and 2020. All cases were registered by the German Diagnosis Related Groups—and the German Operation and Procedure Classification (OPS) system. A uniform search for SVT ablations from 2005 to 2020 with the same OPS codes defining the type of ablation/arrhythmia as well as the presence of a vascular complication, cardiac tamponade, and/or in-hospital death was performed. An overall of 47 610 ablations with 10 037 SVT ablations were registered from 2005 to 2020 among three high-volume centres. An overall complication rate of 0.5% (n = 38) was found [median age, 64; ±15 years; female n = 26 (68%)]. All-cause mortality was 0.02% (n = 2) and both patients had major prior co-morbidities precipitating a lethal outcome irrespective of the ablation procedure. Vascular complications occurred in 10 patients (0.1%), and cardiac tamponade was detected in 26 cases (0.3%).\nConclusion The present case-based analysis shows an overall low incidence of in-hospital complications after SVT ablation highlighting the overall very good safety profile of SVT ablations in high-volume centres. Further prospective analysis is still warranted to guarantee continuous quality control and optimal patient care.\nPermalink\rhttps://doi.org/10.1093/europace/euac146\nhttps://pubmed.ncbi.nlm.nih.gov/36006798\nCite this article:\nDoldi F, Geßler N, Anwar O, Kahle AK, Scherschel K, Rath B, Köbe J, Lange PS, Frommeyer G, Metzner A, Meyer C, Willems S, Kuck KH, Eckardt L. In-hospital mortality and major complications related to radiofrequency catheter ablations of over 10 000 supraventricular arrhythmias from 2005 to 2020: individualized case analysis of multicentric administrative data. Europace. 2023 Feb 8;25(1):130-136. doi: 10.1093/europace/euac146. PMID: 36006798; PMCID: PMC10103566.\n","permalink":"https://scherschel.science/publications/2023-02-08-europace/","summary":"EP Europace","title":"In-hospital mortality and major complications related to radiofrequency catheter ablations of over 10 000 supraventricular arrhythmias from 2005 to 2020: individualized case analysis of multicentric administrative data"},{"content":"Abstract Background The sympathetic nervous system plays an integral role in cardiac physiology. Nerve fibers innervating the left ventricle are amenable to transvenous catheter stimulation along the coronary sinus (CS).\nObjectives The aim of the present study was to modulate left ventricular control by selective intracardiac sympathetic denervation.\nMethods First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of decentralized murine hearts (n = 10 each, ablation and control groups). Second, the impact of transvenous, anatomically driven axotomy by catheter-based radiofrequency ablation via the CS was evaluated in healthy sheep (n = 8) before and during stellate ganglion stimulation.\nResults CS ablation prolonged epicardial ventricular refractory period without (41.8 ± 8.4 ms vs 53.0 ± 13.5 ms; P = 0.049) and with β1-2-adrenergic receptor blockade (47.8 ± 7.8 ms vs 73.1 ± 13.2 ms; P \u0026lt; 0.001) in mice. Supported by neuromorphological studies illustrating a circumferential CS neural network, intracardiac axotomy by catheter ablation via the CS in healthy sheep diminished the blood pressure increase during stellate ganglion stimulation (Δ systolic blood pressure 21.9 ± 10.9 mm Hg vs 10.5 ± 12.0 mm Hg; P = 0.023; Δ diastolic blood pressure 9.0 ± 5.5 mm Hg vs 3.0 ± 3.5 mm Hg; P = 0.039).\nConclusions Transvenous, anatomically driven axotomy targeting nerve fibers along the CS enables acute modulation of left ventricular control by selective intracardiac sympathetic denervation.\nPermalink\rhttps://doi.org/10.1016/j.jacep.2022.10.013\nhttps://pubmed.ncbi.nlm.nih.gov/36752452\nCite this article:\nKahle AK, Klatt N, Jungen C, Dietenberger A, Kuklik P, Münkler P, Willems S, Nikolaev V, Pauza DH, Scherschel K, Meyer C. Acute Modulation of Left Ventricular Control by Selective Intracardiac Sympathetic Denervation. JACC Clin Electrophysiol. 2023 Mar;9(3):371-384. doi: 10.1016/j.jacep.2022.10.013. Epub 2022 Nov 30. PMID: 36752452.\n","permalink":"https://scherschel.science/publications/2022-11-30-jacc-clin-electrophysiol/","summary":"JACC: Clinical Electrophysiology","title":"Acute Modulation of Left Ventricular Control by Selective Intracardiac Sympathetic Denervation"},{"content":"Abstract Background Optimal lesion formation during catheter-based radiofrequency current (RFC) ablation depends on electro-mechanical tip-tissue coupling measurable via contact force (CF) and local impedance (LI) monitoring. We aimed to investigate CF and LI dynamics in patients with previous atrial fibrillation (AF) ablation who frequently present with heterogenous arrhythmia substrate.\nMethods Data from consecutive patients presenting for repeat AF or atrial tachycardia ablation using a novel open-irrigated single-tip ablation catheter were studied. RFC applications were investigated regarding CF, LI and the maximum LI drop (∆LI) for evaluation of ablation efficacy. ∆LI \u0026gt; 20 Ω was defined as a successful RFC application.\nResults A total of 730 RFC applications in 20 patients were analyzed. Baseline CF was not associated with baseline LI (R = 0.06, p = 0.17). A mean CF \u0026lt; 8 g during ablation resulted in lower ∆LI (\u0026lt;8 g: 13 Ω vs. ≥ 8 g: 16 Ω, p \u0026lt; 0.001). Baseline LI showed a better correlation with ∆LI (R = 0.35, p \u0026lt; 0.001) compared to mean CF (R = 0.17, p \u0026lt; 0.001). Mean CF correlated better with ∆LI in regions of low (R = 0.31, p \u0026lt; 0.001) compared to high (R = 0.21, p = 0.02) and intermediate voltage (R = 0.17, p = 0.004). Combined CF and baseline LI predicted ∆LI \u0026gt; 20 Ω (area under the receiver operating characteristic curve (AUC) 0.75) better compared to baseline LI (AUC 0.72), mean CF (AUC 0.60), force-time integral (AUC 0.59) and local bipolar voltage (0.55).\nConclusion Combination of CF and LI may aid monitoring real-time catheter-tissue electro-mechanical coupling and lesion formation within heterogenous atrial arrhythmia substrate in patients with repeat AF or atrial tachycardia ablation.\nPermalink\rhttps://doi.org/10.3389/fphys.2022.1001719\nhttps://pubmed.ncbi.nlm.nih.gov/36311229\nCite this article:\nAlken FA, Scherschel K, Kahle AK, Masjedi M, Meyer C. Combined contact force and local impedance dynamics during repeat atrial fibrillation catheter ablation. Front Physiol. 2022 Oct 13;13:1001719. doi: 10.3389/fphys.2022.1001719. PMID: 36311229; PMCID: PMC9606811.\n","permalink":"https://scherschel.science/publications/2022-10-13-front-physiol/","summary":"Frontiers in Physiology","title":"Combined contact force and local impedance dynamics during repeat atrial fibrillation catheter ablation"},{"content":"Abstract Aims Bipolar radiofrequency ablation (B-RFA) has been reported as a bail-out strategy for the treatment of therapy refractory ventricular arrhythmias (VA). Currently, existing setups have not been standardized for B-RFA, while the impact of conventional B-RFA approaches on lesion formation remains unclear.\nMethods and results (i) In a multicentre observational study, patients undergoing B-RFA for previously therapy-refractory VA using a dedicated B-RFA setup were retrospectively analysed. (ii) Additionally, in an ex vivo model lesion formation during B-RFA was evaluated using porcine hearts. In a total of 26 procedures (24 patients), acute success was achieved in all 14 ventricular tachycardia (VT) procedures and 7/12 procedures with premature ventricular contractions (PVC), with major complications occurring in 1 procedure (atrioventricular block). During a median follow-up of 211 days in 21 patients, 6/11 patients (VT) and 5/10 patients (PVC) remained arrhythmia-free. Lesion formation in the ex vivo model during energy titration from 30 to 50 W led to similar lesion volumes compared with initial high-power 50 W B-RFA. Lesion size significantly increased when combining sequential unipolar and B-RFA (1429 mm3 vs. titration 501 mm3 vs. B-RFA 50 W 423 mm3, P \u0026lt; 0.001), an approach used in overall 58% of procedures and more frequently applied in procedures without VA recurrence (92% vs. 36%, P = 0.009). Adipose tissue severely limited lesion formation during B-RFA.\nConclusion Using a dedicated device for B-RFA for therapy-refractory VA appears feasible and safe. While some patients need repeat ablation, success rates were encouraging. Sequential unipolar and B-RFA may be favourable for lesion formation.\nPermalink\rhttps://doi.org/10.1093/europace/euab304 https://pubmed.ncbi.nlm.nih.gov/34922350\nCite this article:\nKany S, Alken FA, Schleberger R, Baran J, Luik A, Haas A, Ene E, Deneke T, Dinshaw L, Rillig A, Metzner A, Reissmann B, Makimoto H, Reents T, Popa MA, Deisenhofer I, Piotrowski R, Kulakowski P, Kirchhof P, Scherschel K, Meyer C. Bipolar ablation of therapy-refractory ventricular arrhythmias: application of a dedicated approach. Europace. 2022 Jul 15;24(6):959-969. doi: 10.1093/europace/euab304. PMID: 34922350; PMCID: PMC9282917.\n","permalink":"https://scherschel.science/publications/2022-07-15-europace/","summary":"EP Europace","title":"Bipolar ablation of therapy-refractory ventricular arrhythmias: application of a dedicated approach"},{"content":"Abstract Background The importance of peripheral chemoreceptors for cardiorespiratory neural control is known for decades. Pure oxygen inhalation deactivates chemoreceptors and increases parasympathetic outflow. However, the relationship between autonomic nervous system (ANS) activation and resulting respiratory as well as heart rate (HR) dynamics is still not fully understood.\nMethods In young adults the impact of (1) 100 % pure oxygen inhalation (hyperoxic cardiac chemoreflex sensitivity (CHRS) testing), (2) the cold face test (CFT) and (3) the cold pressor test (CPT) on heart rate variability (HRV), hemodynamics and respiratory rate was investigated in randomized order. Baseline ANS outflow was determined assessing respiratory sinus arrhythmia via deep breathing, baroreflex sensitivity and HRV.\nResults Baseline ANS outflow was normal in all participants (23 ± 1 years, 7 females, 3 males). Hyperoxic CHRS testing decreased HR (after 60 ± 3 vs before 63 ± 3 min-1, p = 0.004), while increasing total peripheral resistance (1053 ± 87 vs 988 ± 76 dyne*s + m2/cm5, p = 0.02) and mean arterial blood pressure (93 ± 4 vs 91 ± 4 mm Hg, p = 0.02). HRV indicated increased parasympathetic outflow after hyperoxic CHRS testing accompanied by a decrease in respiratory rate (15 ± 1vs 19 ± 1 min-1, p = 0.001). In contrast, neither CFT nor CPT altered the respiratory rate (18 ± 1 vs 18 ± 2 min-1, p = 0.38 and 18 ± 1 vs 18 ± 1 min-1, p = 0.84, respectively).\nConclusion Changes in HR characteristics during deactivation of peripheral chemoreceptors but not during the CFT and CPT are related with a decrease in respiratory rate. This highlights the need of respiratory rate assessment when evaluating adaptations of cardiorespiratory chemoreceptor control.\nPermalink\rhttps://doi.org/10.1016/j.autneu.2022.103009\nhttps://pubmed.ncbi.nlm.nih.gov/35753247\nCite this article:\nApelt-Glitz K, Alken FA, Jungen C, Scherschel K, Klöcker N, Meyer C. Respiratory and heart rate dynamics during peripheral chemoreceptor deactivation compared to targeted sympathetic and sympathetic/parasympathetic (co-)activation. Auton Neurosci. 2022 Sep;241:103009. doi: 10.1016/j.autneu.2022.103009. Epub 2022 Jun 15. PMID: 35753247.\n","permalink":"https://scherschel.science/publications/2022-06-15-auton-neurosci/","summary":"Autonomic Neuroscience: Basic \u0026amp; Clinical","title":"Respiratory and heart rate dynamics during peripheral chemoreceptor deactivation compared to targeted sympathetic and sympathetic/parasympathetic (co-)activation"},{"content":"\rPermalink\rhttps://doi.org/10.1161/circep.121.010727\nhttps://pubmed.ncbi.nlm.nih.gov/35622433\nCite this article:\nKahle AK, Jungen C, Scherschel K, Alken FA, Meyer C. Relationship Between Early and Late Recurrences After Catheter Ablation for Atrial Tachycardia in Patients With a History of Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2022 Jun;15(6):e010727. doi: 10.1161/CIRCEP.121.010727. Epub 2022 May 27. PMID: 35622433.\n","permalink":"https://scherschel.science/publications/2022-05-27-circ-arrhythm-electrophysiol/","summary":"Circulation: Arrhythmia and Electrophysiology","title":"Relationship Between Early and Late Recurrences After Catheter Ablation for Atrial Tachycardia in Patients With a History of Atrial Fibrillation"},{"content":"Abstract Worldwide, ∼4 million people die from sudden cardiac death every year caused in more than half of the cases by ischaemic cardiomyopathy (ICM). Prevention of sudden cardiac death after myocardial infarction by implantation of a cardioverter-defibrillator (ICD) is the most common, even though not curative, therapy to date. Optimized ICD programming should be strived for in order to decrease the incidence of ICD interventions. Catheter ablation reduces the recurrence of ventricular tachycardias (VTs) and is an important adjunct to sole ICD-based treatment or pharmacological antiarrhythmic therapy in patients with ICM, as conclusively demonstrated by seven randomized controlled trials (RCTs) in the last two decades. However, none of the conducted trials was powered to reveal a survival benefit for ablated patients as compared to controls. Whereas thorough consideration of an early approach is necessary following two recent RCTs (PAUSE-SCD, BERLIN VT), catheter ablation is particularly recommended in patients with recurrent VT after ICD therapy. In this context, novel, pathophysiologically driven ablation strategies referring to deep morphological and functional substrate phenotyping based on high-resolution mapping and three-dimensional visualization of scars appear promising. Emerging concepts like sympathetic cardiac denervation as well as radioablation might expand the therapeutical armamentarium especially in patients with therapy-refractory VT. Randomized controlled trials are warranted and on the way to investigate how these translate into improved patient outcome. This review summarizes therapeutic strategies currently available for the prevention of VT recurrences, the optimal timing of applicability, and highlights future perspectives after a PAUSE in BERLIN.\nPermalink\rhttps://doi.org/10.1093/europace/euab274\nhttps://pubmed.ncbi.nlm.nih.gov/34967892\nCite this article:\nKahle AK, Jungen C, Alken FA, Scherschel K, Willems S, Pürerfellner H, Chen S, Eckardt L, Meyer C. Management of ventricular tachycardia in patients with ischaemic cardiomyopathy: contemporary armamentarium. Europace. 2022 Apr 5;24(4):538-551. doi: 10.1093/europace/euab274. PMID: 34967892.\n","permalink":"https://scherschel.science/publications/2022-04-05-europace/","summary":"EP Europace","title":"Management of ventricular tachycardia in patients with ischaemic cardiomyopathy: contemporary armamentarium"},{"content":"Abstract Fibroblasts contribute to approximately 20% of the non-cardiomyocytic cells in the heart. They play important roles in the myocardial adaption to stretch, inflammation, and other pathophysiological conditions. Fibroblasts are a major source of extracellular matrix (ECM) proteins whose production is regulated by cytokines, such as TNF-α or TGF-β. The resulting myocardial fibrosis is a hallmark of pathological remodeling in dilated cardiomyopathy (DCM). Therefore, in the present study, the secretome and corresponding transcriptome of human cardiac fibroblasts from patients with DCM was investigated under normal conditions and after TNF-α or TGF-β stimulation. Secreted proteins were quantified via mass spectrometry and expression of genes coding for secreted proteins was analyzed via Affymetrix Transcriptome Profiling. Thus, we provide comprehensive proteome and transcriptome data on the human cardiac fibroblast\u0026rsquo;s secretome. In the secretome of quiescent fibroblasts, 58% of the protein amount belonged to the ECM fraction. Interestingly, cytokines were responsible for 5% of the total protein amount in the secretome and up to 10% in the corresponding transcriptome. Furthermore, cytokine gene expression and secretion were upregulated upon TNF-α stimulation, while collagen secretion levels were elevated after TGF-β treatment. These results suggest that myocardial fibroblasts contribute to pro-fibrotic and to inflammatory processes in response to extracellular stimuli.\nPermalink\rhttps://doi.org/10.3390/ijms222212262\nhttps://pubmed.ncbi.nlm.nih.gov/34830141\nCite this article:\nBräuninger H, Thottakara T, Schön J, Voss S, Dhople V, Warnke S, Scherschel K, Schrage B, Kirchhof P, Blankenberg S, Völker U, Westermann D, Hammer E, Lindner D. Cytokine-Mediated Alterations of Human Cardiac Fibroblast\u0026rsquo;s Secretome. Int J Mol Sci. 2021 Nov 12;22(22):12262. doi: 10.3390/ijms222212262. PMID: 34830141; PMCID: PMC8617966.\n","permalink":"https://scherschel.science/publications/2021-11-12-int-j-mol-sci/","summary":"International Journal of Molecular Sciences","title":"Cytokine-Mediated Alterations of Human Cardiac Fibroblast's Secretome"},{"content":"Abstract Aims Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19.\nMethods and results In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset ‘Heart Cell Atlas’ and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value \u0026lt;0.05 (e.g. up: IFI44L, IFT3, TRIM25; down: NPPB, MB, MYPN). The upregulated DEGs were linked to interferon pathways and originate predominantly from endothelial cells. In contrast, the downregulated DEGs originate predominately from cardiomyocytes. Immunofluorescent staining showed viral protein in cells positive for the endothelial marker ICAM1 but rarely in cardiomyocytes. The Gene Ontology (GO) term analysis revealed that downregulated GO terms were linked to cardiomyocyte structure, whereas upregulated GO terms were linked to anti-virus immune response.\nConclusion This study reveals that cardiac infection induced transcriptomic alterations mainly linked to immune response and destruction of cardiomyocytes. While endothelial cells are primarily targeted by the virus, we suggest cardiomyocyte destruction by paracrine effects. Increased pro-inflammatory gene expression was detected in SARS-CoV-2-infected cardiac tissue but no increased SARS-CoV-2 associated immune cell infiltration was observed.\nPermalink\rhttps://doi.org/10.1093/cvr/cvab322\nhttps://pubmed.ncbi.nlm.nih.gov/34647998\nCite this article:\nBräuninger H, Stoffers B, Fitzek ADE, Meißner K, Aleshcheva G, Schweizer M, Weimann J, Rotter B, Warnke S, Edler C, Braun F, Roedl K, Scherschel K, Escher F, Kluge S, Huber TB, Ondruschka B, Schultheiss HP, Kirchhof P, Blankenberg S, Püschel K, Westermann D, Lindner D. Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart. Cardiovasc Res. 2022 Jan 29;118(2):542-555. doi: 10.1093/cvr/cvab322. PMID: 34647998; PMCID: PMC8803085.\n","permalink":"https://scherschel.science/publications/2021-10-14-cardiovasc-res/","summary":"Cardiovascular Research","title":"Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart"},{"content":"Abstract Background Myocardial slow conduction is a cornerstone of ventricular tachycardia (VT). Prolonged electrogram (EGM) duration is a useful surrogate parameter and manual annotation of EGM characteristics are widely used during catheter-based ablation of the arrhythmogenic substrate. However, this remains time-consuming and prone to inter-operator variability. We aimed to develop an algorithm for 3-D visualization of EGM duration relative to the 17-segment American Heart Association model.\nMethods To calculate and visualize EGM duration, in sinus rhythm acquired high-density maps of patients with ischemic cardiomyopathy undergoing substrate-based VT ablation using a 64-mini polar basket-catheter with low noise of 0.01 mV were analyzed. Using a custom developed algorithm based on standard deviation and threshold, the relationship between EGM duration, endocardial voltage and ablation areas was studied by creating 17-segment 3-D models and 2-D polar plots.\nResults 140,508 EGMs from 272 segments (n = 16 patients, 94% male, age: 66±2.4, ejection fraction: 31±2%) were studied and 3-D visualization of EGM duration was performed. Analysis of signal processing parameters revealed that a 40 ms sliding SD-window, 15% SD-threshold and \u0026gt;70 ms EGM duration cutoff was chosen based on diagnostic odds ratio of 12.77 to visualize rapidly prolonged EGM durations. EGMs \u0026gt; 70 ms matched to 99% of areas within dense scar (\u0026lt;0.2 mV), in 95% of zones within scar border zone (0.2–1.0 mV) and detected ablated areas having resulted in non-inducibility at the end of the procedure. Ablation targets were identified with a sensitivity of 65.6% and a specificity of 94.6% avoiding false positive labeling of prolonged EGMs in segments with healthy myocardium.\nConclusion The novel algorithm allows rapid visualization of prolonged EGM durations. This may facilitate more objective characterization of arrhythmogenic substrate in patients with ischemic cardiomyopathy.\nPermalink\rhttps://doi.org/10.1371/journal.pone.0254683\nhttps://pubmed.ncbi.nlm.nih.gov/34260658\nCite this article:\nMasjedi M, Jungen C, Kuklik P, Alken FA, Kahle AK, Klatt N, Scherschel K, Lorenz J, Meyer C. A novel algorithm for 3-D visualization of electrogram duration for substrate-mapping in patients with ischemic heart disease and ventricular tachycardia. PLoS One. 2021 Jul 14;16(7):e0254683. doi: 10.1371/journal.pone.0254683. PMID: 34260658; PMCID: PMC8279369.\n","permalink":"https://scherschel.science/publications/2021-07-14-plos-one/","summary":"PLOS One","title":"A novel algorithm for 3-D visualization of electrogram duration for substrate-mapping in patients with ischemic heart disease and ventricular tachycardia"},{"content":"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.\nPermalink\rhttps://doi.org/10.3390/ijms22094772\nhttps://pubmed.ncbi.nlm.nih.gov/33946275\nCite this article:\nScherschel K, Bräuninger H, Mölders A, Erlenhardt N, Amin E, Jungen C, Pape U, Lindner D, Chetkovich DM, Klöcker N, Meyer C. Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice. Int J Mol Sci. 2021 Apr 30;22(9):4772. doi: 10.3390/ijms22094772. PMID: 33946275; PMCID: PMC8125662.\n","permalink":"https://scherschel.science/publications/2021-04-30-int-j-mol-sci/","summary":"International Journal of Molecular Sciences","title":"Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice"},{"content":"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.\nPermalink\rhttps://doi.org/10.3791/62026\nhttps://pubmed.ncbi.nlm.nih.gov/33427236\nCite this article:\nScherschel K, Bräuninger H, Glufke K, Jungen C, Klöcker N, Meyer C. Location, Dissection, and Analysis of the Murine Stellate Ganglion. J Vis Exp. 2020 Dec 22;(166). doi: 10.3791/62026. PMID: 33427236.\n","permalink":"https://scherschel.science/publications/2020-12-22-j-vis-exp/","summary":"JoVE","title":"Location, Dissection, and Analysis of the Murine Stellate Ganglion"},{"content":"Abstract Aims 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).\nMethods and results The study population consisted of 73 consecutive patients (age: 62.7 ± 10.9 years, 54.8% males) undergoing first-time PVI with either radiofrequency (RF; n = 30) or cryoballoon (CB; n = 43) for paroxysmal AF. S100B determined from venous plasma samples taken immediately before and after PVI increased from 33.5 ± 1.8 to 91.1 ± 5.3 pg/mL (P \u0026lt; 0.0001). S100B release in patients undergoing CB-PVI was 3.9 times higher compared to patients with RF-PVI (ΔS100B: 21.1 ± 2.7 vs. 83.1 ± 5.2 pg/mL, P \u0026lt; 0.0001). During a mean follow-up of 314 ± 186 days, AF recurrences were observed in 18/71 (25.4%) patients (RF-PVI: n = 9/28, CB-PVI: n = 9/43). Univariate Cox regression analysis indicated that an increase in S100B was associated with higher freedom from AF in follow-up (hazard ratio per 10 pg/mL release of S100B: 0.83; 95% confidence interval: 0.72-0.95; P = 0.007).\nConclusion The ablation technique used for PVI has an impact on the release of S100B, a well-established biomarker for neural damage.\nPermalink\rhttps://doi.org/10.1093/europace/euaa159\nhttps://pubmed.ncbi.nlm.nih.gov/32830253\nCite this article:\nScherschel K, Hedenus K, Jungen C, Münkler P, Willems S, Anwar O, Klatt N, Eickholt C, Meyer C. Impact of the ablation technique on release of the neuronal injury marker S100B during pulmonary vein isolation. Europace. 2020 Oct 1;22(10):1502-1508. doi: 10.1093/europace/euaa159. PMID: 32830253; PMCID: PMC7544533.\n","permalink":"https://scherschel.science/publications/2020-10-01-europace/","summary":"EP Europace","title":"Impact of the ablation technique on release of the neuronal injury marker S100B during pulmonary vein isolation"},{"content":"Abstract Introduction 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.\nMethods and Results In 250 consecutive patients (age 66.5 ± 0.7 years, 58% male) with ATs (98% prior catheter ablation, 13% prior cardiac surgery) an HDM-guided catheter ablation was performed with the support of a 64-electrode mini-basket catheter. A total of 354 ATs (1.4 ± 0.1 ATs per patient; mean cycle length 304 ± 4.3 ms; 64% macroreentry, 27% localized reentry, and 9% focal) with acute termination of 95% were targeted in the index procedure. A similar AT as in the index procedure recurred in five patients (2%) after a median follow-up time of 535 days (interquartile range (IQR) 25th–75th percentile: 217–841). Tailored ablation of reentry ATs with freedom from any arrhythmia was obtained in 53% after a single procedure and in 73% after 1.4 ± 0.4 ablation procedures (range: 1–4). A total of 228 patients (91%) were free from any arrhythmia recurrence after 210 days (IQR: 152–494) when including optimal usual care.\nConclusions Tailored catheter ablation of ATs guided by HDM has a high acute success rate. The recurrence rate of the index AT is low. In patients with extensive atrial scaring further ablation procedures need to be considered to achieve freedom from any arrhythmia.\nPermalink\rhttps://doi.org/10.1111/jce.14703\nhttps://pubmed.ncbi.nlm.nih.gov/32748442\nCite this article:\nJungen 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. Outcome after tailored catheter ablation of atrial tachycardia using ultra-high-density mapping. J Cardiovasc Electrophysiol. 2020 Oct;31(10):2645-2652. doi: 10.1111/jce.14703. Epub 2020 Aug 11. PMID: 32748442.\n","permalink":"https://scherschel.science/publications/2020-08-04-j-cardiovasc-electrophysiol/","summary":"Journal of Cardiovascular Electrophysiology","title":"Impact of the ablation technique on release of the neuronal injury marker S100B during pulmonary vein isolation"},{"content":"Abstract Importance 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.\nObjective To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection.\nDesign, setting, and participants This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests.\nExposures Patients who died of coronavirus disease 2019.\nMain outcomes and measures Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3+, CD45+, and CD68+ cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18.\nResults 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.\nConclusions and relevance 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.\nPermalink\rhttps://doi.org/10.1001/jamacardio.2020.3551\nhttps://pubmed.ncbi.nlm.nih.gov/32730555\nCite this article:\nLindner 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. Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. JAMA Cardiol. 2020 Nov 1;5(11):1281-1285. doi: 10.1001/jamacardio.2020.3551. PMID: 32730555; PMCID: PMC7385672.\n","permalink":"https://scherschel.science/publications/2020-07-27-jama-cardiol/","summary":"JAMA Cardiology","title":"Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases"},{"content":"Abstract Background 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.\nMethods 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%.\nResults 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.\nConclusion 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.\nPermalink\rhttps://doi.org/10.1371/journal.pone.0235132\nhttps://pubmed.ncbi.nlm.nih.gov/32584880\nCite this article:\nAnwar O, Gunawardene MA, Dickow J, Scherschel K, Jungen C, Münkler P, Eickholt C, Willems S, Gessler N, Meyer C. 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. 2020 Jun 25;15(6):e0235132. doi: 10.1371/journal.pone.0235132. PMID: 32584880; PMCID: PMC7316283.\n","permalink":"https://scherschel.science/publications/2020-06-25-plos-one/","summary":"PLOS One","title":"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"},{"content":"\rPermalink\rhttps://doi.org/10.1016/j.ijcard.2019.08.023\nhttps://pubmed.ncbi.nlm.nih.gov/31668656\nCite this article:\nScherschel K, Gosau N. EAT: What role does the fat around the heart play? Int J Cardiol. 2020 Feb 15;301:121-122. doi: 10.1016/j.ijcard.2019.08.023. Epub 2019 Sep 5. PMID: 31668656.\n","permalink":"https://scherschel.science/publications/2020-02-15-int-j-cardiol/","summary":"International Journal of Cardiology","title":"EAT: What role does the fat around the heart play?"},{"content":"Abstract Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because 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. 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.\nNew \u0026amp; Noteworthy Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after β-sympathetic blockade.\nPermalink\rhttps://doi.org/10.1152/ajpheart.00249.2019\nhttps://pubmed.ncbi.nlm.nih.gov/31625779\nCite this article:\nJungen C, Scherschel K, Flenner F, Jee H, Rajendran P, De Jong KA, Nikolaev V, Meyer C, Ardell JL, Tompkins JD. Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation. Am J Physiol Heart Circ Physiol. 2019 Dec 1;317(6):H1328-H1341. doi: 10.1152/ajpheart.00249.2019. Epub 2019 Oct 18. PMID: 31625779; PMCID: PMC6962614.\n","permalink":"https://scherschel.science/publications/2019-12-01-am-j-physiol-heart-circ-physiol/","summary":"American Journal of Physiology – Heart and Circulatory Physiology","title":"Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation"},{"content":"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.\nPermalink\rhttps://doi.org/10.1007/s10654-019-00577-4\nhttps://pubmed.ncbi.nlm.nih.gov/31705407\nCite this article:\nJagodzinski 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. Rationale and Design of the Hamburg City Health Study. Eur J Epidemiol. 2020 Feb;35(2):169-181. doi: 10.1007/s10654-019-00577-4. Epub 2019 Nov 8. PMID: 31705407; PMCID: PMC7125064.\n","permalink":"https://scherschel.science/publications/2019-11-08-eur-j-epidemiol/","summary":"European Journal of Epidemiology","title":"Rationale and Design of the Hamburg City Health Study"},{"content":"Abstract Background 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.\nMethods We studied a series of consecutive adult patients with moderate to great CHD complexity and an indication for catheter ablation due to symptomatic arrhythmia. HDM was conducted using the Rhythmia™ mapping system and a 64-electrode mini-basket catheter for identification of anatomy, voltage, activation pattern and critical areas of arrhythmia for ablation guidance. To investigate novel advanced mapping strategies, postprocedural signal processing using the Lumipoint™ software was applied.\nResults In 19 patients (53±3 years; 53% male), 21 consecutive ablation procedures were conducted. Procedures included ablation of atrial fibrillation (n=7; 33%), atrial tachycardia (n=11; 52%), atrioventricular accessory pathway (n=1; 5%), the atrioventricular node (n=1; 5%) and ventricular arrhythmias (n=4; 19%). A total of 23 supraventricular and 8 ventricular arrhythmias were studied with the generation of 56 complete high density maps (atrial n=43; ventricular n=11, coronary sinus n=2) and an average of 12,043±1,679 mapping points. Multiple arrhythmias were observed in n=7 procedures (33% of procedures; range of arrhythmias detected 2-4). A total range of 1-4 critical areas were defined per procedure and treated within a radiofrequency application time of 16 (interquartile range 12-45) minutes. Postprocedural signal processing using Lumipoint™ allowed rapid annotation of fractionated signals within specific windows of interest. This supported identification of a practical critical isthmus in 20 out of 27 completed atrial and ventricular tachycardia activation maps.\nConclusions 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.\nPermalink\rhttps://doi.org/10.21037/cdt.2019.10.02\nhttps://pubmed.ncbi.nlm.nih.gov/31737533\nCite this article:\nAlken 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. Advanced mapping strategies for ablation therapy in adults with congenital heart disease. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S247-S263. doi: 10.21037/cdt.2019.10.02. PMID: 31737533; PMCID: PMC6837939.\n","permalink":"https://scherschel.science/publications/2019-10-28-cardiovasc-diagn-ther/","summary":"Cardiovascular Diagnosis \u0026amp; Therapy","title":"Advanced mapping strategies for ablation therapy in adults with congenital heart disease"},{"content":" Treating the nervous ticker Catheter ablation induces tissue damage in specific regions of the heart in patients with atrial fibrillation (rapid irregular heartbeat) to correct abnormal electrical signals. Although effective, the underlying mechanism remains incompletely understood. Scherschel et al. demonstrated that cryothermal ablation induced release of S100B, a marker of neuronal injury, from glial cells within mouse hearts. S100B stimulated nerve growth and reduced neuronal electrical activity. In patients receiving ablations, higher serum concentration of S100B after the procedure was associated with lower recurrence of atrial fibrillation. Further study is warranted to understand how ablation-induced injury to the intrinsic cardiac autonomic nervous system contributes to patient outcomes.\nAbstract 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.\nPermalink\rhttps://doi.org/10.1126/scitranslmed.aav7770 https://pubmed.ncbi.nlm.nih.gov/31118294\nCite this article:\nScherschel 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. Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation. Sci Transl Med. 2019 May 22;11(493):eaav7770. doi: 10.1126/scitranslmed.aav7770. PMID: 31118294.\n","permalink":"https://scherschel.science/publications/2019-05-22-sci-transl-med/","summary":"Science Translational Medicine","title":"Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation"},{"content":"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.\nPermalink\rhttps://doi.org/10.1016/j.biomaterials.2019.03.023\nhttps://pubmed.ncbi.nlm.nih.gov/30933775\nCite this article:\nSchulze ML, Lemoine MD, Fischer AW, Scherschel K, David R, Riecken K, Hansen A, Eschenhagen T, Ulmer BM. Dissecting hiPSC-CM pacemaker function in a cardiac organoid model. Biomaterials. 2019 Jun;206:133-145. doi: 10.1016/j.biomaterials.2019.03.023. Epub 2019 Mar 21. PMID: 30933775.\n","permalink":"https://scherschel.science/publications/2019-03-29-biomaterials/","summary":"Biomaterials","title":"Dissecting hiPSC-CM pacemaker function in a cardiac organoid model"},{"content":"Abstract Introduction 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.\nMaterial and methods Respiratory sinus arrhythmia, measured by using a deep breathing test and heart rate variability parameters, was studied in 10 patients (64 ±3 years) with paroxysmal AF presenting in stable sinus rhythm for their first catheter-based PVI. Additionally, heart rate dynamics before and after PVI were studied during sympathetic/parasympathetic coactivation by using a cold-face test. All tests were performed within 24 h before and 48 h after PVI.\nResults After PVI RSA (E/I difference: 7.9 ±1.0 vs. 3.5 ±0.6 bpm, p = 0.006; E/I ratio: 1.14 ±0.02 vs. 1.05 ±0.01, p = 0.003), heart rate variability (SDNN: 31 ±3 vs. 14 ±3 ms, p = 0.006; RMSSD: 17 ±2 vs. 8 ±2 ms, p = 0.002) and the HR response to sympathetic/parasympathetic coactivation (10.2 ±0.7% vs. 5.7 ±1.1%, p = 0.014) were diminished. The PVI-related changes in RSA correlated with the heart rate change during sympathetic/parasympathetic coactivation before vs. after PVI (E/I difference: r = 0.849, p = 0.002; E/I ratio: r = 0.786, p = 0.007). One patient with vagal driven arrhythmia experienced AF recurrence during follow-up (mean: 6.5 ±0.6 months).\nConclusions Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.\nPermalink\rhttps://doi.org/10.5114/aoms.2019.83883 https://pubmed.ncbi.nlm.nih.gov/32863990\nCite this article:\nJungen C, Alken FA, Eickholt C, Scherschel K, Kuklik P, Klatt N, Schwarzl J, Moser J, Jularic M, Akbulak RO, Schaeffer B, Willems S, Meyer C. Respiratory sinus arrhythmia is reduced after pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Arch Med Sci. 2019 Mar 25;16(5):1022-1030. doi: 10.5114/aoms.2019.83883. PMID: 32863990; PMCID: PMC7444695.\n","permalink":"https://scherschel.science/publications/2019-03-25-arch-med-sci/","summary":"Archives of Medical Science","title":"Respiratory sinus arrhythmia is reduced after pulmonary vein isolation in patients with paroxysmal atrial fibrillation"},{"content":"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.\nPermalink\rhttps://doi.org/10.3390/biom9020038\nhttps://pubmed.ncbi.nlm.nih.gov/30678084\nCite this article:\nVoss S, Krüger S, Scherschel K, Warnke S, Schwarzl M, Schrage B, Girdauskas E, Meyer C, Blankenberg S, Westermann D, Lindner D. Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts. Biomolecules. 2019 Jan 23;9(2):38. doi: 10.3390/biom9020038. PMID: 30678084; PMCID: PMC6406883.\n","permalink":"https://scherschel.science/publications/2019-01-23-biomolecules/","summary":"Biomolecules","title":"Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts"},{"content":"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.\nPermalink\rhttps://doi.org/10.1007/s00395-018-0701-2\nhttps://pubmed.ncbi.nlm.nih.gov/30178427\nCite this article:\nKrause J, Löser A, Lemoine MD, Christ T, Scherschel K, Meyer C, Blankenberg S, Zeller T, Eschenhagen T, Stenzig J. Rat atrial engineered heart tissue: a new in vitro model to study atrial biology. Basic Res Cardiol. 2018 Sep 3;113(5):41. doi: 10.1007/s00395-018-0701-2. PMID: 30178427.\n","permalink":"https://scherschel.science/publications/2018-09-03-basic-res-cardiol/","summary":"Basic Research in Cardiology","title":"Rat atrial engineered heart tissue: a new in vitro model to study atrial biology"},{"content":"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.\nPermalink\rhttps://doi.org/10.1073/pnas.1721635115\nhttps://pubmed.ncbi.nlm.nih.gov/30166452\nCite this article:\nHinrichs 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. Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction. Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8727-E8736. doi: 10.1073/pnas.1721635115. Epub 2018 Aug 30. PMID: 30166452; PMCID: PMC6140510.\n","permalink":"https://scherschel.science/publications/2018-08-30-proc-natl-acad-sci-usa/","summary":"Proceedings of the National Academy of Sciences of the United States of America","title":"Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction"},{"content":"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.\nPermalink\rhttps://doi.org/10.3791/57617\nhttps://pubmed.ncbi.nlm.nih.gov/29889210\nCite this article:\nJungen C, Scherschel K, Bork NI, Kuklik P, Eickholt C, Kniep H, Klatt N, Willems S, Nikolaev VO, Meyer C. Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System. J Vis Exp. 2018 May 22;(135):57617. doi: 10.3791/57617. PMID: 29889210; PMCID: PMC6101334.\n","permalink":"https://scherschel.science/publications/2018-05-22-j-vis-exp/","summary":"JoVE","title":"Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System"},{"content":"\rPermalink\rhttps://doi.org/10.1152/ajpheart.00061.2017\nhttps://pubmed.ncbi.nlm.nih.gov/28188212\nCite this article:\nMeyer C, Scherschel K. Ventricular tachycardia in ischemic heart disease: the sympathetic heart and its scars. Am J Physiol Heart Circ Physiol. 2017 Mar 1;312(3):H549-H551. doi: 10.1152/ajpheart.00061.2017. Epub 2017 Feb 10. PMID: 28188212.\n","permalink":"https://scherschel.science/publications/2017-03-01-am-j-physiol-heart-circ-physiol/","summary":"American Journal of Physiology – Heart and Circulatory Physiology","title":"Ventricular tachycardia in ischemic heart disease: the sympathetic heart and its scars"},{"content":"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.\nPermalink\rhttps://doi.org/10.1038/ncomms14155\nhttps://pubmed.ncbi.nlm.nih.gov/28128201\nCite this article:\nJungen 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. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias. Nat Commun. 2017 Jan 27;8:14155. doi: 10.1038/ncomms14155. PMID: 28128201; PMCID: PMC5290156.\n","permalink":"https://scherschel.science/publications/2017-01-27-nat-commun/","summary":"Nature Communications","title":"Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias"},{"content":"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\u0026amp;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.\nPermalink\rhttps://doi.org/10.14814/phy2.12897\nhttps://pubmed.ncbi.nlm.nih.gov/27613823\nCite this article:\nKlatt 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. Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model. Physiol Rep. 2016 Sep;4(17):e12897. doi: 10.14814/phy2.12897. PMID: 27613823; PMCID: PMC5027340.\n","permalink":"https://scherschel.science/publications/2016-09-13-physiol-rep/","summary":"Physiological Reports","title":"Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model"},{"content":"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\u0026rsquo;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.\nPermalink\rhttps://doi.org/10.1074/jbc.m114.550509\nhttps://pubmed.ncbi.nlm.nih.gov/24550399\nCite this article:\nPaciotti S, Persichetti E, Klein K, Tasegian A, Duvet S, Hartmann D, Gieselmann V, Beccari T. Accumulation of free oligosaccharides and tissue damage in cytosolic α-mannosidase (Man2c1)-deficient mice. J Biol Chem. 2014 Apr 4;289(14):9611-22. doi: 10.1074/jbc.M114.550509. Epub 2014 Feb 18. PMID: 24550399; PMCID: PMC3975011.\n","permalink":"https://scherschel.science/publications/2014-04-04-j-biol-chem/","summary":"Journal of Biological Chemistry","title":"Accumulation of free oligosaccharides and tissue damage in cytosolic α-mannosidase (Man2c1)-deficient mice"},{"content":"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.\nResults 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\u0026rsquo; or 3\u0026rsquo; 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.\nConclusion 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.\nPermalink\rhttps://doi.org/10.1186/1471-2091-14-2\nhttps://pubmed.ncbi.nlm.nih.gov/23305559\nCite this article:\nBremer S, Klein K, Sedlmaier A, Abouzied M, Gieselmann V, Franken S. Hepatoma-derived growth factor and nucleolin exist in the same ribonucleoprotein complex. BMC Biochem. 2013 Jan 10;14:2. doi: 10.1186/1471-2091-14-2. PMID: 23305559; PMCID: PMC3551658.\n","permalink":"https://scherschel.science/publications/2013-01-10-bmc-biochen/","summary":"BMC Biochemistry","title":"Hepatoma-derived growth factor and nucleolin exist in the same ribonucleoprotein complex"},{"content":"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.\nPermalink\rhttps://doi.org/10.1016/j.bbadis.2012.03.005\nhttps://pubmed.ncbi.nlm.nih.gov/22465033\nCite this article:\nPersichetti E, Klein K, Paciotti S, Lecointe K, Balducci C, Franken S, Duvet S, Matzner U, Roberti R, Hartmann D, Gieselmann V, Beccari T. Lysosomal di-N-acetylchitobiase-deficient mouse tissues accumulate Man2GlcNAc2 and Man3GlcNAc2. Biochim Biophys Acta. 2012 Jul;1822(7):1137-46. doi: 10.1016/j.bbadis.2012.03.005. Epub 2012 Mar 20. PMID: 22465033.\n","permalink":"https://scherschel.science/publications/2012-03-20-biochim-biophys-acta/","summary":"Biochimica et Biophysica Acta","title":"Lysosomal di-N-acetylchitobiase-deficient mouse tissues accumulate Man2GlcNAc2 and Man3GlcNAc2"}]