Transcatheter Closure of Atrial Septal Defect with Carag Bioresorbable Septal Occluder™: First-in-Child Experience with 12-MonthFollow-Up

BACKGROUND Nowadays, transcatheter device closure of an atrial septal defect (ASD) is a standard approach in children. Potential early and long-term side effects or complications related to the metal framework of the devices are a known issue. A bioresorbable device such as the Carag Bioresorbable Septal Occluder™ (CBSO) could resolve such complications. Material and Results. The Carag Bioresorbable Septal Occluder™ (CBSO; Carag AG, Baar, Switzerland) is a self-centering double disk, repositionable, and retractable device with a bioresorbable framework (polylactic-co-glycolic acid), which is almost completely resorbed by 18-24 months postimplantation. This manuscript reports the four first-in-child ASD device closures using a CBSO. The patients' age was median (IQ1-IQ3), 4.5 years (4-7.25). Weight was 21.3 kg (17.6-32.7). We demonstrated procedural feasibility and safety. Effective defect closure with the device was 100%. Echocardiographic measurements of the thickness of the interatrial septum did not show any relevant increase over a 12-monthfollow-up period. There were no residual defects found after the procedure or later during the resorption process. The patients showed no evidence of any local or systemic inflammatory reaction. CONCLUSIONS The CBSO device system could offer a new treatment option for transcatheter ASD device closure in the pediatric and adult fields. In our first-in-child experience, it was effectively and safely implanted. During the first 12 months of follow-up, no complications occurred

Serum dihydrotestosterone is associated with adverse myocardial remodeling in patients with aortic valve stenosis before and after aortic valve replacement

AIMS: Animal studies show a pivotal role of dihydrotestosterone (DHT) in pressure overload induced myocardial hypertrophy and dysfunction. The aim of our study was to evaluate the role of DHT levels and myocardial hypertrophy and myocardial protein expression in patients with severe aortic valve stenosis (AS). METHODS AND RESULTS: 43 patients (median age 68 (41-80) years) with severe AS and indication for surgical aortic valve replacement (SAVR) were prospectively enrolled. Cardiac magnetic resonance imaging including analysis of left ventricular muscle mass (LVM), fibrosis and function and laboratory tests including serum DHT levels were performed before and after SAVR. During SAVR left ventricular (LV) biopsies were performed for proteomic profiling. Serum DHT levels correlated positively with indexed LVM (LVMi, R=0.64, p<0.0001) and fibrosis (R=0.49, p=0.0065) and inversely with LV function (R=-0.42, p=0.005) in patients with severe AS. DHT levels were associated with higher abundance of the hypertrophy (moesin (R=0.52, p=0.0083)) and fibrosis (vimentin (R=0.41, p=0.039)) associated proteins from LV myocardial biopsies. Higher serum DHT levels preoperatively were associated with reduced LV function (ejection fraction: R=-0.34, p=0.035, circulatory efficiency: R=-0.46, p=0.012, global longitudinal strain: R=0.49, p=0.01) and increased fibrosis (R=0.55, p=0.0022) after SAVR. CONCLUSIONS: Serum DHT levels were associated with adverse myocardial remodeling and higher abundance in hypertrophy and fibrosis associated proteins in patients with severe AS. DHT may be a target to prevent or attenuate adverse myocardial remodeling in patients with pressure overload due to AS

Nationwide Registry‐Based Analysis of Infective Endocarditis Risk After Pulmonary Valve Replacement

Background: Infective endocarditis (IE) after pulmonary valve replacements in congenital heart disease is a significant concern. This study aimed to identify specific long-term risk factors for IE after percutaneous pulmonary valve implantation or surgical pulmonary valve replacement. Methods and Results: All patients with congenital heart disease from the National Register for Congenital Heart Defects with at least 1 pulmonary valve replacement before January 2018 were included. A total of 1170 patients (56.3% men, median age at study inclusion 12 [interquartile range {Q1-Q3} 5-20 years]) received 1598 pulmonary valve replacements. IE occurred in 4.8% of patients during a follow-up of total 9397 patient-years (median 10 [Q1-Q3, 6-10] years per patient). After homograft implantation 7 of 558 (1.3%) patients developed IE, after heterograft implantation 31 of 723 (4.3%) patients, and after Melody valve implantation 18 of 241 (7.5%) patients. Edwards Sapien and mechanical valves were used less frequently and remained without IE. The incidence of IE in heterografts excluding Contegra valves was 7 of 278 (2.5%), whereas the incidence of IE in Contegra valves was 24 of 445 (5.4%). The risk of IE was not increased compared with homografts if Contegra valves were excluded from the heterografts (hazard ratio [HR], 2.60; P=0.075). The risk of IE was increased for bovine jugular vein valves, Contegra valves (HR, 6.72; P<0.001), and Melody valves (HR, 5.49; P<0.001), but did not differ between Melody valves and Contegra valves (HR, 1.01; P=0.978). Conclusions: Bovine jugular vein valves have the highest risk of IE, irrespective of the mode of deployment, either surgical or percutaneous

Diurnal variations of BrONO₂ observed by MIPAS-B at midlatitudes and in the Arctic

The first stratospheric measurements of the diurnal variation in the inorganic bromine (Bry) reservoir species BrONO2 around sunrise and sunset are reported. Arctic flights of the balloon-borne Michelson Interferometer for Passive Atmospheric Sounding (MIPAS-B) were carried out from Kiruna (68° N, Sweden) in January 2010 and March 2011 inside the stratospheric polar vortices where diurnal variations of BrONO2 around sunrise have been observed. High nighttime BrONO2 volume mixing ratios of up to 21 pptv (parts per trillion by volume) were detected in late winter 2011 in the absence of polar stratospheric clouds (PSCs). In contrast, the amount of measured BrONO2 was significantly lower in January 2010 due to low available NO2 amounts (for the build-up of BrONO2), the heterogeneous destruction of BrONO2 on PSC particles, and the gas-phase interaction of BrO (the source to form BrONO2) with ClO. A further balloon flight took place at midlatitudes from Timmins (49° N, Canada) in September 2014. Mean BrONO2 mixing ratios of 22 pptv were observed after sunset in the altitude region between 21 and 29 km. Measurements are compared and discussed with the results of a multi-year simulation performed with the chemistry climate model ECHAM5/MESSy Atmospheric Chemistry (EMAC). The calculated temporal variation in BrONO2 largely reproduces the balloon-borne observations. Using the nighttime simulated ratio between BrONO2 and Bry, the amount of Bry observed by MIPAS-B was estimated to be about 21–25 pptv in the lower stratosphere

Acute and midterm outcomes of the post-approval MELODY Registry: a multicentre registry of transcatheter pulmonary valve implantation

AIMS The post-approval MELODY Registry aimed to obtain multicentre registry data after transcatheter pulmonary valve implantation (TPVI) with the Melody™ valve (Medtronic plc.) in a large-scale cohort of patients with congenital heart disease (CHD). METHODS AND RESULTS Retrospective analysis of multicentre registry data after TPVI with the Melody™ valve. Eight hundred and forty-five patients (mean age: 21.0 ± 11.1 years) underwent TPVI in 42 centres between December 2006 and September 2013 and were followed-up for a median of 5.9 years (range: 0-11.0 years). The composite endpoint of TPVI-related events during follow-up (i.e. death, reoperation, or reintervention >48 h after TPVI) showed an incidence rate of 4.2% per person per year [95% confidence interval (CI) 3.7-4.9]. Transcatheter pulmonary valve implantation infective endocarditis (I.E.) showed an incidence rate of 2.3% per person per year (95% CI 1.9-2.8) and resulted in significant morbidity and in nine deaths. In multivariable Cox proportional hazard models, the invasively measured residual right ventricle (RV)-to-pulmonary artery (PA) pressure gradient (per 5 mmHg) was associated with the risk of the composite endpoint (adjusted hazard ratio: 1.21, 95% CI 1.12-1.30; P 2 improved significantly from 36 [interquartile range (IQR) 24-47] to 12 (IQR 7-17) mmHg and 47 to 1%, respectively (P < 0.001 for each). CONCLUSION The post-approval MELODY Registry confirms the efficacy of TPVI with the Melody™ valve in a large-scale cohort of CHD patients. The residual invasively measured RV-to-PA pressure gradient may serve as a target for further improvement in the composite endpoint and TPVI I.E. However, TPVI I.E. remains a significant concern causing significant morbidity and mortality

Pollution trace gases C₂H₆, C₂H₂, HCOOH, and PAN in the North Atlantic UTLS: observations and simulations

Measurements of the pollution trace gases ethane (C2H6), ethyne (C2H2), formic acid (HCOOH), and peroxyacetyl nitrate (PAN) were performed in the North Atlantic upper troposphere and lowermost stratosphere (UTLS) region with the airborne limb imager GLORIA (Gimballed Limb Observer for Radiance Imaging of the Atmosphere) with high spatial resolution down to cloud top. Observations were made during flights with the German research aircraft HALO (High Altitude and LOng Range Research Aircraft) in the frame of the WISE (Wave-driven ISentropic Exchange) campaign, which was carried out in autumn 2017 from Shannon (Ireland) and Oberpfaffenhofen (Germany). Enhanced volume mixing ratios (VMRs) of up to 2.2 ppbv C2H6, 0.2 ppbv C2H2, 0.9 ppbv HCOOH, and 0.4 ppbv PAN were detected during the flight on 13 September 2017 in the upper troposphere and around the tropopause above the British Isles. Elevated quantities of PAN were measured even in the lowermost stratosphere (locally up to 14 km), likely reflecting the fact that this molecule has the longest lifetime of the four species discussed herein. Backward trajectory calculations as well as global three-dimensional Chemical Lagrangian Model of the Stratosphere (CLaMS) simulations with artificial tracers of air mass origin have shown that the main sources of the observed pollutant species are forest fires in North America and anthropogenic pollution in South Asia and Southeast Asia uplifted and moved within the Asian monsoon anticyclone (AMA) circulation system. After release from the AMA, these species or their precursor substances are transported by strong tropospheric winds over large distances, depending on their particular atmospheric lifetime of up to months. Observations are compared to simulations with the atmospheric models EMAC (ECHAM5/MESSy Atmospheric Chemistry) and CAMS (Copernicus Atmosphere Monitoring Service). These models are qualitatively able to reproduce the measured VMR enhancements but underestimate the absolute amount of the increase. Increasing the emissions in EMAC by a factor of 2 reduces the disagreement between simulated and measured results and illustrates the importance of the quality of emission databases used in chemical models

A multi-center study of their physicochemical characteristics, cell culture and in vivo experiments

PVP-capped silver nanoparticles with a diameter of the metallic core of 70 nm, a hydrodynamic diameter of 120 nm and a zeta potential of −20 mV were prepared and investigated with regard to their biological activity. This review summarizes the physicochemical properties (dissolution, protein adsorption, dispersability) of these nanoparticles and the cellular consequences of the exposure of a broad range of biological test systems to this defined type of silver nanoparticles. Silver nanoparticles dissolve in water in the presence of oxygen. In addition, in biological media (i.e., in the presence of proteins) the surface of silver nanoparticles is rapidly coated by a protein corona that influences their physicochemical and biological properties including cellular uptake. Silver nanoparticles are taken up by cell-type specific endocytosis pathways as demonstrated for hMSC, primary T-cells, primary monocytes, and astrocytes. A visualization of particles inside cells is possible by X-ray microscopy, fluorescence microscopy, and combined FIB/SEM analysis. By staining organelles, their localization inside the cell can be additionally determined. While primary brain astrocytes are shown to be fairly tolerant toward silver nanoparticles, silver nanoparticles induce the formation of DNA double-strand-breaks (DSB) and lead to chromosomal aberrations and sister-chromatid exchanges in Chinese hamster fibroblast cell lines (CHO9, K1, V79B). An exposure of rats to silver nanoparticles in vivo induced a moderate pulmonary toxicity, however, only at rather high concentrations. The same was found in precision-cut lung slices of rats in which silver nanoparticles remained mainly at the tissue surface. In a human 3D triple-cell culture model consisting of three cell types (alveolar epithelial cells, macrophages, and dendritic cells), adverse effects were also only found at high silver concentrations. The silver ions that are released from silver nanoparticles may be harmful to skin with disrupted barrier (e.g., wounds) and induce oxidative stress in skin cells (HaCaT). In conclusion, the data obtained on the effects of this well-defined type of silver nanoparticles on various biological systems clearly demonstrate that cell-type specific properties as well as experimental conditions determine the biocompatibility of and the cellular responses to an exposure with silver nanoparticles

Novel aspects of pulmonary valve replacement strategies in congenital heart disease

Viele Patienten mit korrigierten kongenitalen Vitien benötigen im Laufe ihres Lebens einen Pulmonalklappenersatz, um nachteilige Folgen einer Druck- und/oder Volumenbelastung des rechten Ventrikels zu verhindern. Bis vor kurzer Zeit stand dafür nur der chirurgische Pulmonalklappenersatz als Therapiemöglichkeit zur Verfügung. Heutzutage steht bei der Dysfunktion von RVOT-Konduits zusätzlich ein innovatives Verfahren zum katheterinterventionellen perkutanen Pulmonalklappenersatz zur Verfügung. Die vorgelegte Arbeit zur Untersuchung von Homograft-Konduits zeigte eine moderate Prävalenz einer bedeutsamen Klappeninsuffizienz bereits ein Jahr nach chirurgischer Insertion in Pulmonalklappenposition. Weiterhin implizierten die Ergebnisse, dass mechanische Faktoren einen erheblichen Einfluss auf die Klappenfunktion haben könnten. Diese Befunde betonen neben der Komplexität der kardiochirurgischen Therapie von kongenitalen Vitien, bei der eine große Heterogenität der zugrundeliegenden Anatomien besteht, auch die Notwendigkeit von regelmäßigen Kontrolluntersuchungen. Obwohl Homograft-Konduits eine unverzichtbare Quelle für die RVOT-Rekonstruktion bei der Korrektur von kongenitalen Vitien darstellen, könnte für ausgesuchte Patienten die Insertion anderer RVOT-Konduits vorteilhafter sein. Weitere Studien sind erforderlich, um für jeden Patienten den ‚passgenauen’ chirurgischen RVOT-Konduit zu identifizieren. Die Arbeiten zum perkutanen Pulmonalklappenersatz zeigen, dass dieses innovative Verfahren bei verschiedenen Patientengruppen sicher angewendet werden kann und bei den meisten Patienten zu einer klinischen Verbesserung führt. Insbesondere kann dieses Verfahren zum perkutanen Pulmonalklappenersatz die Beständigkeit von zuvor chirurgisch inserierten RVOT-Konduits verlängern und somit die Morbidität in dieser Patientengruppe reduzieren. Die Arbeiten zeigen aber auch kritisch, dass bei dem derzeit verwendeten Verfahren mit Folgekomplikationen und der Notwendigkeit von Reinterventionen gerechnet werden muss. Stentbrüche konnten als die häufigste frühe Komplikation nach perkutanem Pulmonalklappenersatz identifiziert werden. Weiterhin wurden die Stentbrüche nach ihrem Schweregrad klassifi ziert und daran angepasste Handlungsempfehlungen erarbeitet. Eine Indikation zur Reintervention liegt ab dem Schweregrad Typ II vor. Die empfohlene Therapie besteht dabei im wiederholten perkutanen Pulmonalklappenersatz, welcher das stentbezogene frühe Implantatversagen wirksam behandeln kann. Diese schonende Therapiealternative zur kardiochirurgischen Klappenexplantation könnte dazu beitragen, bei inzelnen Patienten die umulative Anzahl von notwendigen kardiochirurgischen Folgeeingriffen zu verringern. Die in den vorgestellten Arbeiten beschriebenen Ergebnisse unterstreichen die Notwendigkeit von weiteren Studien, die sich mit Aspekten des chirurgischen und perkutanen Pulmonalklappenersatzes beschäftigen. Eine aufeinander abgestimmte Kombination beider Therapiemöglichkeiten könnte dazu beitragen, vielen Patienten mit kongenitalen Vitien eine Lebenszeit umspannende Behandlungsstrategie anbieten zu können.Pulmonary valve replacement is performed to protect the right ventricle from pressure and/or volume overload. Novel aspects of pulmonary valve replacement strategies in congenital heart disease are discussed

Estrogen receptors in the human left-ventricular myocardium a novel molecular component in cardiac hypertrophy and heart failure

GesamtdissertationImmer häufiger werden bei Untersuchungen von Herz-Kreislauferkrankungen Geschlechterunterschiede gefunden, so auch in klinischen und tierexperimentellen Studien zu linksventrikulärer Hypertrophie und Herzinsuffizienz. Östrogenrezeptoren (ER) gehörten in tierexperimentellen Studien zu den interessantesten Kandidaten, die zu diesen Befunden beitragen konnten. In der vorliegenden Arbeit wurden nun erstmals Hinweise auf deren Bedeutung in menschlichen Herzen gefunden. In Myokardproben von Patienten mit Aortenklappenstenose waren ERalpha- und ERbeta-mRNA, sowie ERalpha-Protein heraufreguliert. Dabei konnte dem Subtyp ERbeta eine besondere Funktion zugeordnet werden, denn es zeigte sich eine negative Korrelation zwischen den Transkriptmengen von ERbeta und den Transkriptmengen der Calcineurin-Isoformen CnA beta und CnB. Weiterhin war der prozentuale Anstieg der ERbeta-Erhöhung in der Gruppe der Frauen doppelt so hoch wie bei den Männern. Bei dilatativer Kardiomyopathie (DCM) konnte dem Subtyp ERalpha eine hervorgehobene Funktion zugeordnet werden, denn es waren ERalpha-mRNA und -Protein heraufreguliert, nicht aber ERbeta-mRNA. Hingegen wurde für einen SNP in Exon 4 des für ERalpha kodierenden Gens kein Hinweis auf eine funktionelle Bedeutung gefunden. Es zeigte sich keine Assoziation zum kardialen Phänotyp oder vorliegender ERalpha mRNA-Menge. Schließlich fanden sich in humanen kardialen Fibroblasten aus insuffizienten Herzen Hinweise darauf, dass 17beta-Estradiol die Genexpression von ET-1 und ETA-Rezeptor individuell beeinflussen kann. ER stellen somit neue Komponenten im komplexen Zusammenspiel molekularer Mechanismen bei linksventrikulärer Hypertrophie und Herzinsuffizienz dar. Weitere Studien müssen nun die molekularen Signalwege von ER-Wirkungen aufklären, um deren physiologische Bedeutung besser verstehen zu können.Increasingly, clinical and animal studies suggest gender differences in cardiovascular diseases, such as cardiac hypertrophy and heart failure. In animal studies, estrogen receptors (ER) have been implicated as molecular candidates to explain these findings. For the first time, the present study revealed clues as to ER s role in the human myocardium. In left ventricular myocardial samples of patients with aortic valve stenosis (=model for left ventricular hypertrophy), both ER mRNA and ERalpha protein were upregulated. In this entity, ERbeta seemed to play a particular role, since there was a strong inverse relationship between ERbeta and the pro-hypertrophic Calcineurin A beta / CnB mRNA. Moreover, the percent increase in ERbeta mRNA was more pronounced in myocardial samples of female patients than in those of male patients. By contrast, in dilated cardiomyopathy (DCM), ERalpha seemed to be the more prominent molecule. Only ERalpha mRNA and protein were upregulated, whereas ERbeta mRNA was unaltered. A subsequent analysis of a single-nucleotide-polymorphism (SNP) in exon 4 of ERalpha showed no evidence for its functionality, since there was no association to either cardiac phenotype or the amount of ERalpha mRNA. Finally, stimulation of isolated human cardiac fibroblasts from explanted hearts of patients with heart failure - led to an individual response in endothelin-1 (ET-1) and ETA- receptor gene expression. Thus, estrogen receptors (ER) represent a novel component in the complex interplay of molecular mechanisms in cardiac hypertrophy and heart failure. Further studies on ER s molecular pathways are necessary to help identify their impact on ventricular responses to cardiovascular diseases