Publications by authors named "Christian Meyer"

750 Publications

Deep brain stimulation for locomotion in incomplete human spinal cord injury (DBS-SCI): protocol of a prospective one-armed multi-centre study.

BMJ Open 2021 Sep 30;11(9):e047670. Epub 2021 Sep 30.

Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.

Introduction: Spinal cord injury (SCI) is a devastating condition with immediate impact on the individual's health and quality of life. Major functional recovery reaches a plateau 3-4 months after injury despite intensive rehabilitative training. To enhance training efficacy and improve long-term outcomes, the combination of rehabilitation with electrical modulation of the spinal cord and brain has recently aroused scientific interest with encouraging results. The mesencephalic locomotor region (MLR), an evolutionarily conserved brainstem locomotor command and control centre, is considered a promising target for deep brain stimulation (DBS) in patients with SCI. Experiments showed that MLR-DBS can induce locomotion in rats with spinal white matter destructions of >85%.

Methods And Analysis: In this prospective one-armed multi-centre study, we investigate the safety, feasibility, and therapeutic efficacy of MLR-DBS to enable and enhance locomotor training in severely affected, subchronic and chronic American Spinal Injury Association Impairment Scale C patients in order to improve functional recovery. Patients undergo an intensive training programme with MLR-DBS while being regularly followed up until 6 months post-implantation. The acquired data of each timepoint are compared with baseline while the primary endpoint is performance in the 6-minute walking test. The clinical trial protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials checklist.

Ethics And Dissemination: This first in-man study investigates the therapeutic potential of MLR-DBS in SCI patients. One patient has already been implanted with electrodes and underwent MLR stimulation during locomotion. Based on the preliminary results which promise safety and feasibility, recruitment of further patients is currently ongoing. Ethical approval has been obtained from the Ethical Committee of the Canton of Zurich (case number BASEC 2016-01104) and Swissmedic (10000316). Results will be published in peer-reviewed journals and presented at conferences.

Trial Registration Number: NCT03053791.
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http://dx.doi.org/10.1136/bmjopen-2020-047670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487195PMC
September 2021

Initial rhythm control with cryoballoon ablation vs drug therapy: Impact on quality of life and symptoms.

Am Heart J 2021 Sep 8;242:103-114. Epub 2021 Sep 8.

Kerckhoff Heart Center, Bad Nauheim, Germany.

Background: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized.

Methods: Patients aged 18 to 75 with symptomatic paroxysmal AF naïve to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary.

Results: Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs AAD (all P <0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5 -14.2, P <0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P <0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs 15.2 days/year post-blanking; IRR: 0.30, P <0.001).

Conclusions: In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms.

Trial Registration: ClinicalTrials.gov number: NCT01803438.
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http://dx.doi.org/10.1016/j.ahj.2021.08.007DOI Listing
September 2021

Light regulates alternative splicing outcomes via the TOR kinase pathway.

Cell Rep 2021 Sep;36(10):109676

Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología, Molecular, y Celular, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), C1428EHA, Buenos Aires, Argentina. Electronic address:

For plants, light is the source of energy and the most relevant regulator of growth and adaptations to the environment by inducing changes in gene expression at various levels, including alternative splicing. Light-triggered chloroplast retrograde signals control alternative splicing in Arabidopsis thaliana. Here, we provide evidence that light regulates the expression of a core set of splicing-related factors in roots. Alternative splicing responses in roots are not directly caused by light but are instead most likely triggered by photosynthesized sugars. The target of rapamycin (TOR) kinase plays a key role in this shoot-to-root signaling pathway. Knocking down TOR expression or pharmacologically inhibiting TOR activity disrupts the alternative splicing responses to light and exogenous sugars in roots. Consistently, splicing decisions are modulated by mitochondrial activity in roots. In conclusion, by activating the TOR pathway, sugars act as mobile signals to coordinate alternative splicing responses to light throughout the whole plant.
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http://dx.doi.org/10.1016/j.celrep.2021.109676DOI Listing
September 2021

Molecular detection of bla gene to predict phenotypic cephalosporin resistance and clinical outcome of Escherichia coli bloodstream infections in Vietnam.

Ann Clin Microbiol Antimicrob 2021 Sep 4;20(1):60. Epub 2021 Sep 4.

108 Institute of Clinical and Pharmaceutical Sciences, Hanoi, Vietnam.

Background: Blood stream infections (BSI) caused by Extended Spectrum Beta-Lactamases (ESBLs) producing Enterobacteriaceae is a clinical challenge leading to high mortality, especially in developing countries. In this study, we sought to describe the epidemiology of ESBL-producing Escherichia coli strains isolated from Vietnamese individuals with BSI, to investigate the concordance of genotypic-phenotypic resistance, and clinical outcome of ESBL E. coli BSI.

Methods: A total of 459 hospitalized patients with BSI were screened between October 2014 and May 2016. 115 E. coli strains from 115 BSI patients were isolated and tested for antibiotic resistance using the VITEK®2 system. The ESBL phenotype was determined by double disk diffusion method following the guideline of Clinical and Laboratory Standards Institute. Screening for beta-lactamase (ESBL and carbapenemase) genes was performed using a multiplex-PCR assay.

Results: 58% (67/115) of the E. coli strains were ESBL-producers and all were susceptible to both imipenem and meropenem. Resistance to third-generation cephalosporin was common, 70% (81/115) were cefotaxime-resistant and 45% (52/115) were ceftazidime-resistant. bla was the most common ESBL gene detected (70%; 80/115) The sensitivity and specificity of bla-detection to predict the ESBL phenotype was 87% (76-93% 95% CI) and 54% (39-48% 95% CI), respectively. 28%% (22/80) of bla were classified as non-ESBL producers by phenotypic testing for ESBL production. The detection of bla in ESBL-negative E. coli BSI was associated with fatal clinical outcome (27%; 6/22 versus 8%; 2/26, p = 0.07).

Conclusion: A high prevalence of ESBL-producing E. coli isolates harbouring bla was observed in BSI patients in Vietnam. The genotypic detection of bla may have added benefit in optimizing and guiding empirical antibiotic therapy of E. coli BSI to improve clinical outcome.
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http://dx.doi.org/10.1186/s12941-021-00466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418716PMC
September 2021

The small GTPase KlRho5 responds to oxidative stress and affects cytokinesis.

J Cell Sci 2021 Sep 24;134(18). Epub 2021 Sep 24.

Universität Osnabrück, Fachbereich Biologie/Chemie, AG Genetik, Barbarastr. 11, D-49076 Osnabrück, Germany.

Rho5 is the yeast homolog of the human small GTPase Rac1. We characterized the genes encoding Rho5 and the subunits of its dimeric activating guanine-nucleotide-exchange factor (GEF), Dck1 and Lmo1, in the yeast Kluyveromyces lactis. Rapid translocation of the three GFP-tagged components to mitochondria upon oxidative stress and carbon starvation indicate a similar function of KlRho5 in energy metabolism and mitochondrial dynamics as described for its Saccharomyces cerevisiae homolog. Accordingly, Klrho5 deletion mutants are hyper-resistant towards hydrogen peroxide. Moreover, synthetic lethalities of rho5 deletions with key components in nutrient sensing, such as sch9 and gpr1, are not conserved in K. lactis. Instead, Klrho5 deletion mutants display morphological defects with strengthened lateral cell walls and protruding bud scars. The latter result from aberrant cytokinesis, as observed by following the budding process in vivo and by transmission electron microscopy of the bud neck region. This phenotype can be suppressed by KlCDC42G12V, which encodes a hyper-active variant. Data from live-cell fluorescence microscopy support the notion that KlRho5 interferes with the actin moiety of the contractile actomyosin ring, with consequences different from those previously reported for mutants lacking myosin.
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http://dx.doi.org/10.1242/jcs.258301DOI Listing
September 2021

Impact of comorbidities on acute kidney injury and renal function impairment after partial and radical tumor nephrectomy.

Scand J Urol 2021 Oct 24;55(5):377-382. Epub 2021 Aug 24.

Department of Urology, University Medical Center Göttingen, Göttingen, Germany.

Background: To test for the impact of patient comorbidities and medical risk factors on kidney function after partial (PN) or radical nephrectomy (RN) in renal cell carcinoma (RCC) patients with normal preoperative renal function.

Materials And Methods: From January 2011 to December 2014, 195 consecutive RCC patients with a preoperative estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m underwent PN or RN. Stratification was performed according to postoperative acute kidney injury (AKI) vs. no AKI. Moreover, logistic regression models tested for risk factors predicting postoperative AKI and subsequent new-onset chronic kidney disease (eGFR < 60 or < 45 ml/min/1.73 m).

Results: Of all eligible patients, 127 (65.1%) exhibited AKI. AKI patients underwent more frequently RN (44.9 vs. 13.2% PN) and harbored more often preoperative diabetes (17.3 vs. 5.9% no diabetes), hypertension (46.5 vs. 23.5% no hypertension) and larger median tumor size (4.5 vs. 2.5 cm, all  < 0.05) than non-AKI patients. Moreover, after median follow-up of 14 months, 18.9% of AKI patients exhibited an eGFR < 60 ml/min/1.73 m vs. 7.4% non-AKI patients ( = 0.01). In multivariable models, hypertension and RN were risk factors for postoperative AKI (both  < 0.01). Age > 60 years and RN as well as preoperative diabetes were risk factors for postoperative eGFR < 60 or < 45 ml/min/1.73 m (all  < 0.05), respectively.

Conclusions: Postoperative AKI is a non-negligible event especially after RN that can be further triggered by comorbidities such as diabetes and hypertension. Comorbidities should be considered in clinical decision-making for RCC surgery and patients need to be counseled about the increased risk of consecutive renal function impairment.
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http://dx.doi.org/10.1080/21681805.2021.1948916DOI Listing
October 2021

Outcomes of conduction system pacing compared to right ventricular pacing as a primary strategy for treating bradyarrhythmia: systematic review and meta-analysis.

Clin Res Cardiol 2021 Aug 19. Epub 2021 Aug 19.

Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.

Background: Right ventricular pacing (RVP) may cause electrical and mechanical desynchrony leading to impaired left ventricular ejection fraction (LVEF). We investigated the outcomes of RVP with His bundle pacing (HBP) and left bundle branch pacing (LBBP) for patients requiring a de novo permanent pacemaker (PPM) for bradyarrhythmia.

Methods And Results: Systematic review of randomized clinical trials and observational studies comparing HBP or LBP with RVP for de novo PPM implantation between 01 January 2013 and 17 November 2020 was performed. Random and fixed effects meta-analyses of the effect of pacing technology on outcomes were performed. Study outcomes included all-cause mortality, heart failure hospitalization (HFH), LVEF, QRS duration, lead revision, atrial fibrillation, procedure parameters, and pacing metrics. Overall, 9 studies were included (6 observational, 3 randomised). HBP compared with RVP was associated with decreased HFH (risk ratio [RR] 0.68, 95% confidence interval [CI] 0.49-0.94), preservation of LVEF (mean difference [MD] 0.81, 95% CI - 1.23 to 2.85 vs. - 5.72, 95% CI - 7.64 to -3.79), increased procedure duration (MD 15.17 min, 95% CI 11.30-19.04), and increased lead revisions (RR 5.83, 95% CI 2.17-15.70, p = 0.0005). LBBP compared with RVP was associated with shorter paced QRS durations (MD 5.6 ms, 95% CI - 6.4 to 17.6) vs. (51.0 ms, 95% CI 39.2-62.9) and increased procedure duration (MD 37.78 min, 95% CI 20.04-55.51).

Conclusion: Of the limited studies published, this meta-analysis found that HBP and LBBP were superior to RVP in maintaining physiological ventricular activation as an initial pacing strategy.
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http://dx.doi.org/10.1007/s00392-021-01927-7DOI Listing
August 2021

Catheter ablation vs. antiarrhythmic drugs as 'first-line' initial therapy for atrial fibrillation: a pooled analysis of randomized data.

Europace 2021 Aug 18. Epub 2021 Aug 18.

Cardioangiologisches Centrum Bethanien (CCB), Kardiologie, Medizinische Klinik III, Agaplesion Markus Krankenhaus, Akademisches Lehrkrankenhaus der Goethe-Universität Frankfurt am Main, Wilhelm-Epstein Straße 4, Frankfurt am Main 60431, Germany.

Aims: Catheter ablation (CA) is recommended for patients with atrial fibrillation (AF) after failure of antiarrhythmic drugs (AADs). The role of CA as 'initial therapy' for AF is to be determined.

Methods And Results: Following PRISMA guideline an up-to-date pooled analysis of randomized data comparing ablation vs. AADs as first-line therapy for symptomatic AF was performed. The primary outcome was recurrence of atrial tachyarrhythmia. The secondary outcomes were improvement in quality-of-life (QoL) and major adverse events. A total of 997 patients from five randomized trials were enrolled (mean age 57.4 years, 68.6% male patients, 98% paroxysmal AF, mean follow-up 1.4 years). The baseline characteristics were similar between the ablation and AADs group. Overall pooled analysis showed that, as compared with AADs, CA as first-line therapy was associated with significantly higher freedom from arrhythmia recurrence (69% vs. 48%, odds ratio: 0.36, 95% confidence interval: 0.27-0.48, P < 0.001). This significance was maintained in subgroup analyses of 1- and 2-year follow-up (P < 0.001). Catheter ablation was associated with significantly greater improvement in QoL regarding AFEQT score and 36-Item Short-Form Health Survey score. The incidence of serious adverse events between ablation and AADs group (5.6% vs. 4.9%, P = 0.62) was similar.

Conclusions: Catheter ablation as 'initial therapy' was superior to AADs in maintenance of sinus rhythm and improving QoL for patients with symptomatic paroxysmal AF, without increasing risk of serious adverse events.
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http://dx.doi.org/10.1093/europace/euab185DOI Listing
August 2021

Anesthetic Technique (Spinal vs. General Anesthesia) in Holmium Laser Enucleation of the Prostate: Retrospective Analysis of Procedural and Functional Outcomes among 1,159 Patients.

Urol Int 2021 Aug 17:1-8. Epub 2021 Aug 17.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: The aim of the study was to compare procedural efficacy, early and late functional outcomes in holmium laser enucleation of the prostate (HoLEP) under spinal anesthesia (SA) versus general anesthesia (GA).

Methods: We retrospectively reviewed patients undergoing HoLEP at our institution between 2012 and 2017. Standard pre-, peri-, and postoperative characteristics were compared according to anesthetic technique. Multivariable logistic regression analyses (MVAs) were employed to study the impact of SA on procedural efficacy and postoperative complications.

Results: Our study cohort consisted of 1,159 patients, of whom 374 (32%) underwent HoLEP under SA. While a medical history of any anticoagulation/antiplatelet therapy except low-dose acetylsalicylic acid was significantly more common among patients undergoing GA (16% vs. 10%, p = 0.001), no other significant differences in preoperative characteristics were noted including age, body mass index, American Society of Anesthesiologists Classification (ASA), prostate size, or International Prostate Symptom Score (IPSS), and quality of life scores. Patients under SA exhibited shorter times of enucleation 42 min (interquartile range [IQR]:27-59 vs. 45 min [IQR: 31-68], p = 0.002), and combined time of enucleation/morcellation/coagulation (57 min [IQR: 38-85] vs. 64 min [IQR: 43-93], p = 0.002), as well as fewer complications (Clavien-Dindo ≥3) (12 [3.2%] vs. 55 [7%], p = 0.013). These associations were confirmed in MVA. Patients did not differ significantly with regard to early micturition including post-void residual volume and maximum flow-rate improvement. At a median follow-up of 33 months (IQR: 32-44), patients with SA had a lower IPSS score (median 3 [IQR: 1-6] vs. 4 [IQR: 2-7], p = 0.039). However, no significant differences were observed with respect to any urinary incontinence, urge symptoms, and postoperative pain.

Conclusion: In this large retrospective series, HoLEP under SA was a safe and efficacious procedure with comparable early and long-term functional outcomes.
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http://dx.doi.org/10.1159/000517542DOI Listing
August 2021

Spatial concentration and distribution of phase singularities in human atrial fibrillation: Insights for the AF mechanism.

J Arrhythm 2021 Aug 19;37(4):922-930. Epub 2021 Jun 19.

College of Medicine and Public Health Flinders University of South Australia Adelaide SA Australia.

Background: Atrial fibrillation (AF) is characterized by the repetitive regeneration of unstable rotational events, the pivot of which are known as phase singularities (PSs). The spatial concentration and distribution of PSs have not been systematically investigated using quantitative statistical approaches.

Objectives: We utilized a geospatial statistical approach to determine the presence of local spatial concentration and global clustering of PSs in biatrial human AF recordings.

Methods: 64-electrode conventional basket (~5 min, n = 18 patients, persistent AF) recordings were studied. Phase maps were produced using a Hilbert-transform based approach. PSs were characterized spatially using the following approaches: (i) local "hotspots" of high phase singularity (PS) concentration using Getis-Ord Gi* ( ≥ 1.96,  ≤ .05) and (ii) global spatial clustering using Moran's (inverse distance matrix).

Results: Episodes of AF were analyzed from basket catheter recordings (H: 41 epochs, 120 000 s, n = 18 patients). The Getis-Ord Gi* statistic showed local PS hotspots in 12/41 basket recordings. As a metric of spatial clustering, Moran's showed an overall mean of 0.033 (95% CI: 0.0003-0.065), consistent with the notion of complete spatial randomness.

Conclusion: Using a systematic, quantitative geospatial statistical approach, evidence for the existence of spatial concentrations ("hotspots") of PSs were detectable in human AF, along with evidence of spatial clustering. Geospatial statistical approaches offer a new approach to map and ablate PS clusters using substrate-based approaches.
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http://dx.doi.org/10.1002/joa3.12547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339121PMC
August 2021

Longitudinal measurement invariance of the patient health questionnaire in a German sample.

BMC Psychiatry 2021 08 4;21(1):386. Epub 2021 Aug 4.

Department of Social Medicine and Prevention, Institute of Community Medicine, University Medicine Greifswald, Walther-Rathenau-Str. 48, 17475, Greifswald, Germany.

Background: The Patient Health Questionnaire-8 (PHQ-8) is a screening questionnaire of depressive symptoms. However, it is unknown whether it is equivalent across time and between groups of individuals. The aim of our paper was to test whether the PHQ-8 has the same meaning in two groups of individuals over time.

Methods: Primary care patients were proactively recruited from three German cities. PHQ-8 data from a baseline assessment (n = 588), two assessments during the intervention (n = 246/225), and a six (n = 437) and 12 months (n = 447) follow-up assessment were first used to examine the factor structure of the PHQ-8 by confirmatory factor analysis (CFA). The best fitting factor solution was then used to test longitudinal invariance across time and between intervention and control group by Multiple Group CFA.

Results: A two-factor structure consistently showed the best model fit. Only configural longitudinal invariance was evidenced when the baseline assessment was included in the analysis. Without the baseline assessment, strict longitudinal invariance was shown across the intervention and the follow-up assessments. Scalar invariance was established between the intervention and control group for the baseline assessment and strict invariance between groups and across the 6- and 12-month follow-up assessments.

Conclusions: The lack of longitudinal invariance might be attributed to various differences between the baseline assessments and all following assessments, e.g., assessment mode (iPad vs telephone), potential changes in symptom perception, and setting.

Trial Registration: DRKS0001163 5, date of trial registration: 20.01.2017; DRKS00011637 , date of trial registration: 25.01.2017.
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http://dx.doi.org/10.1186/s12888-021-03390-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335884PMC
August 2021

MuSyC is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery.

Nat Commun 2021 07 29;12(1):4607. Epub 2021 Jul 29.

Department of Biochemistry, Vanderbilt University Nashville, Nashville, TN, USA.

Drug combination discovery depends on reliable synergy metrics but no consensus exists on the correct synergy criterion to characterize combined interactions. The fragmented state of the field confounds analysis, impedes reproducibility, and delays clinical translation of potential combination treatments. Here we present a mass-action based formalism to quantify synergy. With this formalism, we clarify the relationship between the dominant drug synergy principles, and present a mapping of commonly used frameworks onto a unified synergy landscape. From this, we show how biases emerge due to intrinsic assumptions which hinder their broad applicability and impact the interpretation of synergy in discovery efforts. Specifically, we describe how traditional metrics mask consequential synergistic interactions, and contain biases dependent on the Hill-slope and maximal effect of single-drugs. We show how these biases systematically impact synergy classification in large combination screens, potentially misleading discovery efforts. Thus the proposed formalism can provide a consistent, unbiased interpretation of drug synergy, and accelerate the translatability of synergy studies.
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http://dx.doi.org/10.1038/s41467-021-24789-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322415PMC
July 2021

High anatomical accuracy of a novel high-resolution wide-band dielectric imaging system in cryoballoon-based ablation.

Pacing Clin Electrophysiol 2021 Sep 28;44(9):1504-1515. Epub 2021 Jul 28.

Department of Cardiology, Universitäres Herz- und Gefäßzentrum Hamburg-Eppendorf, Hamburg, Germany.

Purpose: Recently, a novel cardiac imaging system based on a wide-band dielectric technology (KODEX-EPD) was introduced to guide catheter ablation. The aim of the study was to evaluate this 3D wide-band dielectric imaging system (WDIS) during cryoballoon (CB)-based atrial fibrillation (AF) ablation focusing on accuracy of pulmonary vein (PV)-anatomy.

Methods: In consecutive patients with symptomatic AF, CB-based ablation was performed in conjunction with the 3D WDIS. Selective PV-angiographies were performed, and 3D anatomy of the left atrium (LA) and PVs using the 3D WDIS was created. The ostial diameters of the ipsilateral right-sided and left-sided PVs and ostial diameters of the right-/left-sided upper/lower PVs demonstrated by selective angiographies were analyzed and compared to 3D WDIS-based PV visualization.

Results: In 65 patients (42/65 (65%) male, age 65 ± 9 years, 29/65 (45%) paroxysmal AF) a total of 260 PVs were identified. Median ostial PV-diameters for the ipsilateral left- and right-sided PVs were 38 [34; 43] and 37 [34; 40.3] mm when assessed fluoroscopically and 40 [35.7; 43] and 39 [35.0; 43] mm as demonstrated by 3D WDIS. There was no statistically significant difference between both methods regarding PV-diameter measurements. KODEX-EPD overestimated fluoroscopy measurements by 1.08 mm (95% limits of agreement of -1.93 mm and 4.1 mm).

Conclusion: The novel wide-band dielectric 3D-imaging system is feasible to create high-resolution images of cardiac structures during CB ablation procedures and accurately visualizes PV-anatomy.
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http://dx.doi.org/10.1111/pace.14324DOI Listing
September 2021

Apraglutide, a novel glucagon-like peptide-2 analog, improves fluid absorption in patients with short bowel syndrome intestinal failure: Findings from a placebo-controlled, randomized phase 2 trial.

JPEN J Parenter Enteral Nutr 2021 Jul 20. Epub 2021 Jul 20.

Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome-associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF.

Methods: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6-10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period.

Results: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490-939; P < .05) and 795 ml/day (95% CI, 195-1394; P < .05), respectively, compared with placebo, with no significant differences between doses.

Conclusions: Once-weekly apraglutide was well tolerated at both tested doses and significantly increased urine volume output, providing evidence for increased intestinal fluid absorption. A phase 3 trial is underway in adults with SBS-IF.
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http://dx.doi.org/10.1002/jpen.2223DOI Listing
July 2021

Cystatin C predicts renal function impairment after partial or radical tumor nephrectomy.

Int Urol Nephrol 2021 Oct 16;53(10):2041-2049. Epub 2021 Jul 16.

Department of Urology, University Medical Center Göttingen, Göttingen, Germany.

Purpose: To test the value of preoperative and postoperative cystatin C (CysC) as a predictor on kidney function after partial (PN) or radical nephrectomy (RN) in renal cell carcinoma (RCC) patients with normal preoperative renal function.

Methods: From 01/2011 to 12/2014, 195 consecutive RCC patients with a preoperative estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m underwent surgical RCC treatment with either PN or RN. Logistic and linear regression models tested for the effect of CysC as a predictor of new-onset chronic kidney disease in follow-up (eGFR < 60 ml/min/1.73m). Moreover, postoperative CysC and creatinine values were compared for kidney function estimation.

Results: Of 195 patients, 129 (66.2%) underwent PN. In postoperative and in follow-up setting (median 14 months, IQR 10-20), rates of eGFR < 60 ml/min/1.73m were 55.9 and 30.2%. In multivariable logistic regression models, preoperative CysC [odds ratio (OR): 18.3] and RN (OR: 13.5) were independent predictors for a reduced eGFR < 60 ml/min/1.73m in follow-up (both p < 0.01), while creatinine was not. In multivariable linear regression models, a difference of the preoperative CysC level of 0.1 mg/dl estimated an eGFR decline in follow-up of about 5.8 ml/min/1.73m. Finally, we observed a plateau of postoperative creatinine values in the range of 1.2-1.3 mg/dl, when graphically depicted vs. postoperative CysC values ('creatinine blind area').

Conclusion: Preoperative CysC predicts renal function impairment following RCC surgery. Furthermore, CysC might be superior to creatinine for renal function monitoring in the early postoperative setting.
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http://dx.doi.org/10.1007/s11255-021-02957-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463386PMC
October 2021

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 14;16(7):e0254683. Epub 2021 Jul 14.

Department of Cardiology, Angiology and Intensive Care, EVK Düsseldorf, cNEP, cardiac Neuro- and Electrophysiology Research Consortium, Düsseldorf, Germany.

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.

Methods: 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.

Results: 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 >70 ms EGM duration cutoff was chosen based on diagnostic odds ratio of 12.77 to visualize rapidly prolonged EGM durations. EGMs > 70 ms matched to 99% of areas within dense scar (<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.

Conclusion: The novel algorithm allows rapid visualization of prolonged EGM durations. This may facilitate more objective characterization of arrhythmogenic substrate in patients with ischemic cardiomyopathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279369PMC
July 2021

Genetic and Clinical Predictors of Left Atrial Thrombus: A Single Center Case-Control Study.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:10760296211021171

Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany.

Left atrial (LA) thrombus formation is the presumed origin of thromboembolic complications in patients with atrial fibrillation (AF). Beyond clinical risk factors, the factors causing formation of LA thrombi are not well known. In this case-control study, we analyzed clinical characteristics and genetic thrombophilia markers (factor V Leiden (FVL), prothrombin G20210A (FIIV), Tyr2561 variant of von Willebrand factor (VWF-V)) in 42 patients with AF and LA thrombus (LAT) and in 68 control patients with AF without LAT (CTR). Patients with LAT had more clinical conditions predisposing to stroke (mean CHADS-VASc-score 3.4 ± 1.5 vs. 1.9 ± 1.4; < 0.001), a higher LA volume (96 ± 32 vs. 76 ± 21 ml, = 0.002) and lower LA appendage emptying velocity (0.21 ± 0.11vs. 0.43 ± 0.19 m/s, < 0.001). Prevalence of FVL, FIIV and VWF-V mutations was not different, but in the subgroup of patients <65 years (y) there was a tendency for a higher incidence of VWF-V with a prevalence of 27% (LAT <65 y) vs. 7% (CTR <65 y, = 0.066). These findings warrant further investigation of the VWF-V as a risk factor for LA thrombogenesis in younger patients.
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http://dx.doi.org/10.1177/10760296211021171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246465PMC
June 2021

Electrophysiological Characteristics of Intra-Atrial Reentrant Tachycardia in Adult Congenital Heart Disease: Implications for Catheter Ablation.

J Am Heart Assoc 2021 07 14;10(13):e020835. Epub 2021 Jun 14.

Division of Cardiology Department of Medicine University of California at Los Angeles Medical Center, Ahmanson/Adult Congenital Heart Disease Center Los Angeles CA.

Background Ultra-high-density mapping enables detailed mechanistic analysis of atrial reentrant tachycardia but has yet to be used to assess circuit conduction velocity (CV) patterns in adults with congenital heart disease. Methods and Results Circuit pathways and central isthmus CVs were calculated from consecutive ultra-high-density isochronal maps at 2 tertiary centers over a 3-year period. Circuits using anatomic versus surgical obstacles were considered separately and pathway length <50th percentile identified small circuits. CV analysis was used to derive a novel index for prediction of postablation conduction block. A total of 136 supraventricular tachycardias were studied (60% intra-atrial reentrant, 14% multiple loop). Circuits with anatomic versus surgical obstacles featured longer pathway length (119 mm; interquartile range [IQR], 80-150 versus 78 mm; IQR, 63-95; <0.001), faster central isthmus CV (0.1 m/s; IQR, 0.06-0.25 versus 0.07 m/s; IQR, 0.05-0.10; =0.016), faster non-isthmus CV (0.52 m/s; IQR, 0.33-0.71 versus 0.38 m/s; IQR, 0.27-0.46; =0.009), and fewer slow isochrones (4; IQR, 2.3-6.8 versus 6; IQR 5-7; =0.008). Both central isthmus (=0.45; <0.001) and non-isthmus CV (=0.71; <0.001) correlated with pathway length, whereas central isthmus CV <0.15 m/s was ubiquitous for small circuits. Non-isthmus CV in tachycardia correlated with CV during block validation (=0.94; <0.001) and a validation map to tachycardia conduction time ratio >85% predicted isthmus block in all cases. Over >1 year of follow-up, arrhythmia-free survival was better for homogeneous CV patterns (90% versus 57%; =0.04). Conclusions Ultra-high-density mapping-guided CV analysis distinguishes atrial reentrant patterns in adults with congenital heart disease with surgical obstacles producing slower and smaller circuits. Very slow central isthmus CV may be essential for atrial tachycardia maintenance in small circuits, and non-isthmus conduction time in tachycardia appears to be useful for rapid assessment of postablation conduction block.
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http://dx.doi.org/10.1161/JAHA.121.020835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403273PMC
July 2021

Improved survival among hospitalized patients with COVID-19 treated with remdesivir and dexamethasone. A nationwide population-based cohort study.

Clin Infect Dis 2021 Jun 10. Epub 2021 Jun 10.

Department of Medicine, Zealand University Hospital, Roskilde, Denmark.

Background: There is limited data on outcomes of moderate to severe Coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting.

Objective: To compare the effectiveness of standard of care (SOC) alone vs SOC plus remdesivir and dexamethasone.

Methods: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI).

Results: The 30-d mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI, 0.38-0.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36 (95% CI, 0.29-0.46)).

Conclusions And Relevance: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.
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http://dx.doi.org/10.1093/cid/ciab536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344480PMC
June 2021

Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures.

J Immunother Cancer 2021 06;9(6)

Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA

Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.
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http://dx.doi.org/10.1136/jitc-2021-002345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190056PMC
June 2021

Hydroxychloroquine as a primary prophylactic agent against SARS-CoV-2 infection: A cohort study.

Int J Infect Dis 2021 Jul 1;108:370-376. Epub 2021 Jun 1.

Section of Respiratory Medicine, Department of Medicine, Copenhagen University Hospital Herlev and Gentofte Hospital, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; PERSIMUNE & CHIP: Department of Infectious Diseases, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

Objective: Hydroxychloroquine has been proposed as a primary prophylactic agent against coronavirus disease 2019 (COVID-19). This study aimed to investigate if patients treated with hydroxychloroquine for a non-COVID-19 indication had a lower risk of verified infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared with matched controls.

Methods: A cohort comprising all persons in Denmark collecting hydroxychloroquine prescriptions in 2020 and 2019 (i.e., both during and before SARS-CoV-2 was confirmed in Denmark), matched by age and sex with controls, was studied. Data were collected using the Danish national registries, which contain complete information on patient health data, prescriptions and microbiological test results. The main outcome was microbiologically verified SARS-CoV-2 infection.

Results: In total, 5488 hydroxychloroquine users were matched with 54,486 non-users. At baseline, the groups differed in terms of diagnoses of pulmonary disease, cardiovascular disease, renal disease, gastrointestinal/metabolic disease and dementia, as well as treatment with antirheumatic drugs. The final model was adjusted for these potential confounders. Use of hydroxychloroquine for non-COVID-19 indications was not associated with any change in confirmed SARS-CoV-2 (hazard ratio 0.90, 95% confidence interval 0.76-1.07). This result was robust in the propensity-score-matched sensitivity analysis.

Conclusion: This study, which is the largest to date to investigate the primary prophylactic effect of hydroxychloroquine against SARS-CoV-2, does not support any prophylactic benefit of hydroxychloroquine in the prevention of infection with SARS-CoV-2.
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http://dx.doi.org/10.1016/j.ijid.2021.05.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168303PMC
July 2021

Machine Learning Establishes Single-Cell Calcium Dynamics as an Early Indicator of Antibiotic Response.

Microorganisms 2021 May 5;9(5). Epub 2021 May 5.

BioFrontiers and MCDB Department, University of Colorado Boulder, Boulder, CO 80303, USA.

Changes in bacterial physiology necessarily precede cell death in response to antibiotics. Herein we investigate the early disruption of Ca homeostasis as a marker for antibiotic response. Using a machine learning framework, we quantify the temporal information encoded in single-cell Ca dynamics. We find Ca dynamics distinguish kanamycin sensitive and resistant cells before changes in gross cell phenotypes such as cell growth or protein stability. The onset time (pharmacokinetics) and probability (pharmacodynamics) of these aberrant Ca dynamics are dose and time-dependent, even at the resolution of single-cells. Of the compounds profiled, we find Ca dynamics are also an indicator of Polymyxin B activity. In Polymyxin B treated cells, we find aberrant Ca dynamics precedes the entry of propidium iodide marking membrane permeabilization. Additionally, we find modifying membrane voltage and external Ca concentration alters the time between these aberrant dynamics and membrane breakdown suggesting a previously unappreciated role of Ca in the membrane destabilization during Polymyxin B treatment. In conclusion, leveraging live, single-cell, Ca imaging coupled with machine learning, we have demonstrated the discriminative capacity of Ca dynamics in identifying antibiotic-resistant bacteria.
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http://dx.doi.org/10.3390/microorganisms9051000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148219PMC
May 2021

Prolonged Glucagon Infusion Does Not Affect Energy Expenditure in Individuals with Overweight/Obesity: A Randomized Trial.

Obesity (Silver Spring) 2021 06;29(6):1003-1013

Translational Research Institute, AdventHealth, Orlando, Florida, USA.

Objective: The aim of this study was to determine the effects of prolonged (72 hours) glucagon administration at a low dose (LD) (12.5 ng/kg/min) and high dose (HD) (25 ng/kg/min) on energy expenditure (EE) in healthy individuals with overweight or obesity.

Methods: Thirty-one healthy participants with overweight or obesity (BMI of 27-45 kg/m , 26-55 years old, 23 females) were randomized into LD, HD, or placebo groups and underwent 72-hour intravenous infusion of glucagon. Whole-room calorimetry was used to assess EE and substrate use during five overnight stays (2 days at baseline, 3 days of infusion) and during two 24-hour stays (baseline vs. day 3). Blood was sampled at regular intervals throughout the inpatient stay and analyzed for glucagon and biomarkers of metabolism.

Results: HD infusion elevated plasma glucagon levels compared with the placebo and LD infusion (P < 0.001). Sleeping, basal, and 24-hour EE was not significantly different among groups at any time point. Those receiving HD had significantly higher basal fat oxidation (Fat Ox) at days 2 and 3 than those receiving the placebo (P < 0.05); however, no differences in 24-hour Fat Ox were observed among groups (baseline vs. day 3).

Conclusions: An HD plasma glucagon infusion over 72 hours does not increase any aspects of EE in healthy individuals with overweight or obesity.
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http://dx.doi.org/10.1002/oby.23141DOI Listing
June 2021

Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes.

J Immunother Cancer 2021 05;9(5)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Background: Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.

Methods: 66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung 'PM interface' and 'PM interior' regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection.

Results: IHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS.

Conclusions: Osteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144029PMC
May 2021

Neuroscientific therapies for atrial fibrillation.

Cardiovasc Res 2021 Jun;117(7):1732-1745

University of California Los Angeles (UCLA) Cardiac Arrhythmia Center, David Geffen School of Medicine, UCLA, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.
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http://dx.doi.org/10.1093/cvr/cvab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208752PMC
June 2021

Translational investigation of electrophysiology in hypertrophic cardiomyopathy.

J Mol Cell Cardiol 2021 08 3;157:77-89. Epub 2021 May 3.

Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany. Electronic address:

Hypertrophic cardiomyopathy (HCM) patients are at increased risk of ventricular arrhythmias and sudden cardiac death, which can occur even in the absence of structural changes of the heart. HCM mouse models suggest mutations in myofilament components to affect Ca homeostasis and thereby favor arrhythmia development. Additionally, some of them show indications of pro-arrhythmic changes in cardiac electrophysiology. In this study, we explored arrhythmia mechanisms in mice carrying a HCM mutation in Mybpc3 (Mybpc3-KI) and tested the translatability of our findings in human engineered heart tissues (EHTs) derived from CRISPR/Cas9-generated homozygous MYBPC3 mutant (MYBPC3hom) in induced pluripotent stem cells (iPSC) and to left ventricular septum samples obtained from HCM patients. We observed higher arrhythmia susceptibility in contractility measurements of field-stimulated intact cardiomyocytes and ventricular muscle strips as well as in electromyogram recordings of Langendorff-perfused hearts from adult Mybpc3-KI mice than in wild-type (WT) controls. The latter only occurred in homozygous (Hom-KI) but not in heterozygous (Het-KI) mouse hearts. Both Het- and Hom-KI are known to display pro-arrhythmic increased Ca myofilament sensitivity as a direct consequence of the mutation. In the electrophysiological characterization of the model, we observed smaller repolarizing K currents in single cell patch clamp, longer ventricular action potentials in sharp microelectrode recordings and longer ventricular refractory periods in Langendorff-perfused hearts in Hom-KI, but not Het-KI. Interestingly, reduced K channel subunit transcript levels and prolonged action potentials were already detectable in newborn, pre-hypertrophic Hom-KI mice. Human iPSC-derived MYBPC3hom EHTs, which genetically mimicked the Hom-KI mice, did exhibit lower mutant mRNA and protein levels, lower force, beating frequency and relaxation time, but no significant alteration of the force-Ca relation in skinned EHTs. Furthermore, MYBPC3hom EHTs did show higher spontaneous arrhythmic behavior, whereas action potentials measured by sharp microelectrode did not differ to isogenic controls. Action potentials measured in septal myectomy samples did not differ between patients with HCM and patients with aortic stenosis, except for the only sample with a MYBPC3 mutation. The data demonstrate that increased myofilament Ca sensitivity is not sufficient to induce arrhythmias in the Mybpc3-KI mouse model and suggest that reduced K currents can be a pro-arrhythmic trigger in Hom-KI mice, probably already in early disease stages. However, neither data from EHTs nor from left ventricular samples indicate relevant reduction of K currents in human HCM. Therefore, our study highlights the species difference between mouse and human and emphasizes the importance of research in human samples and human-like models.
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http://dx.doi.org/10.1016/j.yjmcc.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320769PMC
August 2021

Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.

Sarcoma 2021 17;2021:6681741. Epub 2021 Apr 17.

Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma.

Methods: The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence.

Results: In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3,  = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change,  = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%.

Conclusions: Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.
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http://dx.doi.org/10.1155/2021/6681741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068528PMC
April 2021

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). Epub 2021 Apr 30.

Division of Cardiology, EVK Düsseldorf, cNEP, Cardiac Neuro- and Electrophysiology Research Consortium, Kirchfeldstrasse 40, 40217 Düsseldorf, Germany.

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.
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http://dx.doi.org/10.3390/ijms22094772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125662PMC
April 2021
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