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Aims Environmental stressors such as traffic noise represent a global threat, accounting for 1.6 million healthy life years lost annually in Western Europe. Therefore, the noise-associated health side effects must be effectively prevented or mitigated. Non-pharmacological interventions such as physical activity or a balanced healthy diet are effective due to the activation of the adenosine monophosphate-activated protein kinase (α1AMPK). Here, we investigated for the first time in a murine model of aircraft noise-induced vascular dysfunction the potential protective role of α1AMPK activated via exercise, intermittent fasting, and pharmacological treatment. Methods and results Wild-type (B6.Cg-Tg(Cdh5-cre)7Mlia/J) mice were exposed to aircraft noise [maximum sound pressure level of 85 dB(A), average sound pressure level of 72 dB(A)] for the last 4 days. The α1AMPK was stimulated by different protocols, including 5-aminoimidazole-4-carboxamide riboside application, voluntary exercise, and intermittent fasting. Four days of aircraft noise exposure produced significant endothelial dysfunction in wild-type mice aorta, mesenteric arteries, and retinal arterioles. This was associated with increased vascular oxidative stress and asymmetric dimethylarginine formation. The α1AMPK activation with all three approaches prevented endothelial dysfunction and vascular oxidative stress development, which was supported by RNA sequencing data. Endothelium-specific α1AMPK knockout markedly aggravated noise-induced vascular damage and caused a loss of mitigation effects by exercise or intermittent fasting. Conclusion Our results demonstrate that endothelial-specific α1AMPK activation by pharmacological stimulation, exercise, and intermittent fasting effectively mitigates noise-induced cardiovascular damage. Future population-based studies need to clinically prove the concept of exercise/fasting-mediated mitigation of transportation noise-associated disease.

The selective norepinephrine reuptake inhibitor atomoxetine is potentially among the first-line pharmacotherapy options for ADHD. Therapeutic drug monitoring (TDM) with the quantification and interpretation of atomoxetine serum concentrations is used to determine an individual dose followed by an optimal effectiveness and minimal side effects. The aim of this retrospective pharmacokinetic–pharmacodynamic analysis was to derive age-appropriate recommendations for the implementation of TDM to improve the efficacy and tolerability of atomoxetine in children and adolescents. Using the analytical method of high-performance liquid chromatography with UV detection, 94 serum concentrations of 74 patients between 6 and 21 years of age were determined. Therapeutic effectiveness and side effects were evaluated according to the categories “low”, “moderate”, and “significant”. As part of TDM, a time interval with maximum concentrations of 1–3 h after the administration of atomoxetine was determined for blood sampling. In this time interval, a significant correlation between the weight-normalized dose and the serum concentrations was found. The efficacy as well as the tolerability proved to be mainly moderate or significant. A preliminary therapeutic reference range was between 100 and 400 ng/ml. Naturalistic studies have limitations. Therefore, and due to a limited study population, the results have to be regarded as preliminary observations that must be confirmed in further studies. The preliminary therapeutic reference range for children and adolescents proved to be narrower than the reference range for adult patients. However, due to good efficacy and tolerability an exact reference range remained difficult to determine.

Mitral regurgitation (MR) is common in patients with heart failure and constitutes an independent risk factor for adverse prognosis besides NYHA-class. The predictive value of dyspnea reduction after transcatheter mitral valve repair (TMVr) on outcome has not been investigated up to now.We enrolled 627 consecutive patients (47.0% female, 57.4% functional MR; median follow-up 486 days[IQR 157/961]; survival status available in 96.8%; symptoms assessed in n = 556 at baseline / n = 406 at 1 month) treated with isolated percutaneous mitral valve edge-to-edge repair in our center from 06/2010-03/2018 (exclusion of combined forms of TMVr) in a monocentric retrospective analysis. Survival was 97.6% at discharge, 73.9% after 1, 54.5% after 3, 37.6% after 5 and 21.7% after 7-years. Before TMVr, NYHA-classes III/IV were found in 89.0%. Of these, 74.7% reported symptomatic relief (reduction in NYHA-class) one month after procedure (NYHA class recorded in 406 patients at 30 days). NYHA-classes III/IV were documented in 37.2% (p 0.001) at 30 days and in 36.6% (p 0.001) at 1 year without significant changes between the follow-ups. Dyspnea reduction was accompanied by significantly improved long-term survival (1 year, 89.1 vs 71.2%, p = 0.001, 2 years: 75.5 vs 58.7%, p = 0.039) and was identified as an independent predictor for lower mortality (1-year HR for increased mortality by missing symptomatic improvement 2.94 [95%CI 1.53-5.65], p = 0.001; long-term HR 1.95 [95%CI 1.29-2.94], p = 0.001) independently in both etiologies of MR.TMVr by edge-to-edge therapy enables early and sustainable symptomatic improvement in nearly 75% of the symptomatic patients. The simple assessment of postinterventional changes in NYHA-class might serve as an independent predictor for mid- and long-term prognosis in both FMR and DMR.

Zusammenfassung. Fragestellung: Kinder haben ein Recht auf Mitbestimmung. Welche Phasen und Bereiche von Mitbestimmung innerhalb der Kinder- und Jugendpsychiatrie besonders relevant sind, wurde nur selten empirisch untersucht. Somit ist es Ziel der vorliegenden Studie, den Wunsch und das Erleben von Beteiligung für verschiedene Dimensionen der stationären Behandlung in der Kinder- und Jugendpsychiatrie differenziert zu betrachten. Methode: Es wurde eine prospektive multizentrische Fragebogenerhebung durchgeführt. Das Erhebungsinstrument umfasste 100 Fragen, zusammengefasst in 16 Skalen, zum Wunsch und Erleben von Beteiligung innerhalb verschiedener Phasen (Information, Deliberation, Entscheidung), Bereiche (Behandlung, Klinikalltag, Persönliche Freiheiten) und Partizipation im weiteren Sinne (Respekt, Vertrauen). Die Daten wurden deskriptiv und inferenzstatistisch ausgewertet. Ergebnisse: 81 Kinder und Jugendliche aus fünf psychiatrischen Kliniken nahmen an der Studie teil. Insgesamt wünschen sie sich mehr Beteiligung als sie erleben. Je höher die Stufe der Beteiligung, desto größer die Differenz zwischen Wunsch und Erleben. Für Entscheidungen zur Kommunikation mit Familie und Freunden ist der Wunsch nach Beteiligung besonders hoch. Die deutlichste Differenz zwischen Wunsch und Erleben zeigte sich im respektvollen und vertrauensvollen Umgang mit den Kindern und Jugendlichen. Für weibliche Patienten ist diese Differenz noch größer als für männliche. Schlussfolgerung: Partizipation ist mehr als Aufklärung bei Behandlungsentscheidungen. Besonders bei höheren Stufen von Beteiligung und bei Entscheidungen zur Kommunikation mit Familie und Freunden besteht noch Potenzial für den Einbezug der Kinder und Jugendlichen. Ein respekt- und vertrauensvoller Umgang mit den Patientinnen und Patienten, unabhängig von Alter, Geschlecht und Erkrankung, sind dabei die Grundlage.

Background Concomitant tricuspid regurgitation (TR) is a common finding in mitral regurgitation (MR). Transcatheter repair (TMVR) is a favorable treatment option in patients at elevated surgical risk. To date, evidence on long-term prognosis and the prognostic impact of TR after TMVR is limited. Methods Long-term survival data of patients undergoing isolated edge-to-edge repair from June 2010 to March 2018 (combinations with other forms of TMVR or tricuspid valve therapy excluded) were analyzed in a retrospective monocentric study. TR severity was categorized and the impact of TR on survival was analysed. Results Overall, 606 patients [46.5% female, 56.4% functional MR (FMR)] were enrolled in this study. TR at baseline was categorized severe/medium/mild/no or trace in 23.2/34.3/36.3/6.3% of the cases. At 30-day follow-up, improvement of at least one TR-grade was documented in 34.9%. Severe TR at baseline was identified as predictor of 1-year survival [65.2% vs. 77.0%, p = 0.030; HR for death 1.68 (95% CI 1.12–2.54), p = 0.013] and in FMR-patients also regarding long-term prognosis [adjusted HR for long-term mortality 1.57 (95% CI 1.00–2.45), p = 0.049]. Missing post-interventional reduction of TR severity was predictive for poor prognosis, especially in the FMR-subgroup [1-year survival: 92.9% vs. 78.3%, p = 0.025; HR for death at 1-year follow-up 3.31 (95% CI 1.15–9.58), p = 0.027]. While BNP levels decreased in both subgroups, TR reduction was associated with improved symptomatic benefit (NYHA-class-reduction 78.6 vs. 65.9%, p = 0.021). Conclusion In this large study, both, severe TR at baseline as well as missing secondary reduction were predictive for impaired long-term prognosis, especially in patients with FMR etiology. TR reduction was associated with increased symptomatic benefit. Graphic abstract

The number of MitraClip® implantations increased significantly in recent years. Data regarding the impact of weight class on survival are sparse.We hypothesized that weight class influences survival of patients treated with MitraClip® implantation.We investigated in-hospital, 1-year, 3-year, and long-term survival of patients successfully treated with isolated MitraClip® implantation for mitral valve regurgitation (MR) (June 2010-March 2018). Patients were categorized by weight classes, and the impact of weight classes on survival was analyzed.Of 617 patients (aged 79.2 years; 47.3% females) treated with MitraClip® implantation (June 2010-March 2018), 12 patients were underweight (2.2%), 220 normal weight (40.1%), 237 overweight (43.2%), and 64 obesity class I (11.7%), 12 class II (2.2%), and 4 class III (0.7%). Preprocedural Logistic EuroScore (21.1 points [IQR 14.0-37.1]; 26.0 [18.5-38.5]; 26.0 [18.4-39.9]; 24.8 [16.8-33.8]; 33.0 [25.9-49.2]; 31.6 [13.1-47.6]; p = .291) was comparable between groups. Weight class had no impact on in-hospital death (0.0%; 4.1%; 1.5%; 0.0%; 7.7%; 0.0%; p = .189), 1-year survival (75.0%; 72.0%; 76.9%; 75.0%; 75.0%; 33.3%; p = .542), and 3-year survival (40.0%; 36.8%; 38.2%; 48.6%; 20.0%; 33.3%; p = .661). Compared to normal weight, underweight (hazard ratio [HR]: 1.35 [95% confidence interval [CI]: 0.65-2.79], p = .419), obesity-class I (HR: 0.93 [95% CI: 0.65-1.34], p = .705), class II (HR: 0.39 [95% CI: 0.12-1.24], p = .112), and class III (HR: 1.28 [95% CI: 0.32-5.21], p = .726) did not affect long-term survival. In contrast, overweight was associated with better survival (HR: 1.32 [95% CI: 1.04-1.68], p = .023).Overweight affected the long-term survival of patients undergoing MitraClip® implantation beneficially compared to normal weight.

Aims With the present study, we sought to determine the safety of three different endomyocardial biopsy (EMB) access routes in 514 patients admitted for diagnostic workup of heart failure of unknown aetiology. Methods and results In this retrospective monocentric cohort study, we analysed 514 consecutive patients with heart failure without evidence of significant coronary artery disease or valvular disease undergoing EMB between November 2013 and December 2018, stratified in three access route groups: transradial arterial left ventricular (LV‐)EMB (323 patients), transfemoral LV‐EMB (138 patients), and transfemoral right ventricular (RV‐)EMB (53 patients). Patients undergoing selective transradial LV‐EMB were older compared with patients undergoing selective transfemoral LV‐EMB or RV‐EMB [transradial LV‐EMB: 56.0 (45.0/64.0) vs. transfemoral LV‐EMB: 53 (42.5/64.5), P = 0.455; transradial LV‐EMB: 56 (45.0/64.0) vs. RV‐EMB: 53 (42.5/64), P = 0.695] and presented more often in New York Heart Association‐functional class III and IV. A total of eight major complications including permanent atrioventricular block requiring pacemaker implantation, pericardial tamponade necessitating pericardiocentesis, stroke and transient cerebral ischaemic attack as well as severe valvular damage, vascular access site complications, and ventricular fibrillation were documented with no significant differences between the groups (8/514, 1.5%). Minor complications such as transient chest pain, non‐sustained electrocardiogram abnormalities, and transient atrioventricular block were rare and equally distributed between groups. Conclusions Transradial LV‐EMB is a safe procedure for experienced radial operators and non‐inferior compared with transfemoral LV‐EMB and RV‐EMB. An accurate peri‐procedural and post‐procedural monitoring and follow‐up care should be recommended for all patients undergoing this procedure in order to identify potential complications.

Aims The aim of this study was to compare five-year clinical outcomes between an everolimus-eluting bioresorbable scaffold (BRS) and an everolimus-eluting metallic stent (EES) in STEMI patients. Methods and results This observational and retrospective study included 235 consecutive STEMI patients treated with BRS, compared with 235 STEMI patients treated with EES from the EXAMINATION trial, by applying propensity score matching. The primary endpoint was a device-oriented endpoint (DOCE), including cardiac death, target vessel myocardial infarction and target lesion revascularisation at five-year follow-up. Device thrombosis, according to the ARC criteria, was also evaluated. Optical coherence tomography (OCT) analysis was also performed at five years in event-free BRS patients. The cumulative incidence of five-year DOCE was higher in the BRS group as compared to the EES group (13.2% vs 7.6%, HR 1.87, 95% CI: 0.94-3.44, p=0.071), mainly driven by a higher rate of TLR (7.6% vs 1.7%, HR 1.15, 95% CI: 0.44-2.30, p=0.004). The five-year definite BRS thrombosis rate was also higher as compared to EES (4.2% vs 1.2%, HR 3.49, 95% CI: 0.95-12.82, p=0.054). OCT analysis showed a high incidence of neoatherosclerosis in the BRS group. Conclusions The five-year event risk was higher with BRS versus EES in STEMI. This suggests that the probability of obtaining favourable results at very long-term follow-up is low. Whether better results will be obtained with new-generation BVS remains to be determined.

Objective: Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow, which is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. In this study, we determine the role of PGC1α (peroxisome proliferator gamma coactivator-1α)-TERT (telomerase reverse transcriptase)-HMOX1 (heme oxygenase-1) during shear stress in vitro and in vivo. Approach and Results: Here, we have identified PGC1α as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared with oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) showed increased PGC1α expression and its transcriptional coactivation. PGC1α was required for laminar FSS-induced expression of TERT in vitro and in vivo via its association with ERRα(estrogen-related receptor alpha) and KLF (Kruppel-like factor)-4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status, HMOX1 was required for endothelial alignment to laminar FSS. Conclusions: These data suggest an important role for a PGC1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

Introduction Diabetes mellitus (DM) represents a notable risk factor after surgical and interventional procedures but data on the influence of DM on long-term survival after Transcatheter Edge-to-edge Repair (TEER) for Mitral valve Regurgitation (MR) are sparse. Purpose To compare the outcome of patients with and without DM after TEER. Methods Retrospective monocentric assessment of patients after successful treatment of MR by TEER (exclusion of combined forms of transcatheter repair) between 06/2010 and 03/2018. Patients were stratified for DM at baseline and observed regarding mortality during follow-up. Cox regression analyses were performed for survival analyses. Results 627 patients (47.0% females, 88.2% aged ≥70 years) and among these 174 subjects with DM (27.3%) were included with a median follow-up period of 486 days [IQR 157–916 days]). Within the investigation period, 20 patients (3.2%) were lost to follow-up. Patients with DM more often presented severe comorbidities like obesity (27.3% vs. 9.2%, p Conclusions Even though DM-patients presented with a more vulnerable clinical profile, no relevant differences in short- and long-term mortality after TEER for MR were found. Although being factored in most common risk scores, DM could not be associated with an adverse prognosis after transcatheter therapy of MR. Funding Acknowledgement Type of funding sources: None.

Background A symptomatic and prognostic benefit by Transcatheter edge-to-edge repair (TEER) for mitral regurgitation (MR) has been proven. A variety of individual factors including female sex has been suggested to be associated with adverse outcome in cardio-surgical procedures. Purpose While gender is factored in common risk factor models for adverse outcome, evidence on sex-specific differences in long-term outcome after TEER for MR is limited. We aimed to investigate the impact of gender on prognosis in a large monocentric cohort with long-term follow-up. Methods We analyzed survival stratified for gender after successful isolated edge-to-edge repair of MR in the period between 06/2010 and 03/2018 (exclusion of combined forms of TMVR) in a monocentric retrospective cohort by performing survival analyses and cox regression analyses. Results Consecutively, 627 patients (47.0% females, 57.4% functional MR; survival status was available in 96.7%) entered the study and were followed for a median follow-up period of 462 days [IQR 142–945 days]. Survival rates were 97.6% at discharge, 75.7% after 1, 54.5% after 3, 37.6% after 5 and 21.7% after 7 years. Risk score as calculated by the Logistic Euroscore I did not differ significantly between females and males (at baseline: 25.0 [IQR 18.0/34.8] vs. 27.0 [18.4/40.1]%, p=0.093) and no relevant differences were found for in-hospital (2.0 vs. 2.7%, p=0.613), 30 days (4.8 vs. 6.5%, p=0.473) and 1-year mortality (27.0 vs. 25.3%, p=0.675). At the time of procedure, women were older (79.9 [IQR 75.6/84.4] vs. 78.3 [72.9/83.4] years, p Conclusion In our cohort of patients undergoing TEER for MR, we found no evidence for an impaired short- and mid-term prognosis for female patients. In contrary and not as indicated by Logistic Euroscore, female sex was associated with better long-term survival in comparison to men despite higher median age, which might be partly explained by a slightly more favorable cardiovascular risk profile. Funding Acknowledgement Type of funding sources: None. Figure 1

The aim of this study was to compare patients with transcatheter aortic valve replacement (TAVR) receiving new generation prostheses SAPIEN 3 (S3, Edwards Lifesc.) and Evolut R (ER, Medtronic Inc.) in terms of periprocedural and long-term outcome. Our retrospective, single-center analysis included 359 consecutive patients with severe aortic stenosis who underwent TAVR with S3 or ER from 2014–2016 (mean age 82 ± 7 years, 47% male, mean EuroSCORE II 8.0 ± 8%, mean follow-up 3.8 years). Device Success was equal (S3 93.0% vs. ER 92.4%, p = 0.812). We report a 30-day mortality of 2.8% in the S3 group, and 2.1% in the ER group (p = 0.674). There was no difference in stroke, conversion to open surgery, vascular and bleeding complications or myocardial infarction. While prosthesis mean gradients were higher with S3 (12.0 mmHg vs. 8.2 mmHg, p &lt, 0.001), there was a trend to less paravalvular regurgitation (PVR moderate or severe: 1% vs. 3.6%, p = 0.088). All-cause mortality up to 5 years did not show a difference (mean survival S3 3.5 ± 0.24 years, ER 3.3 ± 0.29 years, p = 0.895). Independent predictors of long-term mortality were impaired LVEF, chronic kidney injury, peripheral artery disease, malignant tumor and periprocedural stroke. New generation TAVR valves offer an excellent implant and outcome success rate. Long-term survival was independent of prostheses choice and mainly attributed to comorbidities and complications.

Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow that is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. Here we have identified peroxisome proliferator gamma coactivator-1α (PGC-1α) as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared to oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) increased PGC-1α expression and its transcriptional co-activation. PGC-1α was required for laminar FSS-induced expression of telomerase reverse transcriptase (TERT) in vitro and in vivo via its association with ERRα and KLF4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status was heme oxygenase-1 (HMOX1), a gene required for endothelial alignment to laminar FSS. Thus, these data suggest an important role for a PGC-1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

The desire and the experience of participation among children and adolescents in inpatient mental healthcare

Radiation protection is essential for staff of cardiac catheterization laboratories in order to prevent long-term radiation- associated injury and disease. Instant feedback about the actual received dose may help operators to optimize the use of existing shielding devices. Therefore, the current study was designed to investigate whether routine use of real-time dosimetry may be able to reduce staff radiation exposure.Over a period of 72 days, operators and assisting nurses were equipped with RaySafe i3 real-time dosimeters (Unfors RaySafe AB), but had no access to the dosimetry results during the first half of the study. This was followed by a second period that allowed operators to modify their behavior according to the dosimetry results. Compared with the first phase, the knowledge of real-time dosimetry results led to a uniform reduction in radiation exposure of all team members by approximately 60%, independent of the chosen vascular access. There were no significant changes in fluoroscopy time, dose-area product, or patient characteristics.Real-time dosimetry effectively reduced staff radiation exposure in the cardiac catheterization laboratory. This change was caused by optimized use of existing shielding equipment since no modifications of the general procedural approach or patient characteristics had occurred.

AIMS The number of percutaneous edge-to-edge mitral regurgitation valve repairs with MitraClip implantation has increased during recent years. Published studies showed promising safety outcomes in relatively small cohorts, while results from large samples are sparse. Thus, we aimed to evaluate trends and safety outcomes in the German nationwide in-patient sample. METHODS AND RESULTS We analysed data on patients' characteristics and in-hospital safety outcomes for all percutaneous mitral valve repairs using the MitraClip technique in Germany between 2011 and 2015. Overall, 13,575 in-patients were included. The annual number of MitraClip implantations increased from 815 in 2011 to 4,432 in 2015 (β 1.00 [95% CI: 0.96-1.03], p

ObjectiveApproximately 3.4% of adults aged >75 years suffer from aortic stenosis (AS). Guideline indications for aortic valve replacement (AVR) distinguish between patients with symptomatic and asymptomatic severe AS. The present analysis aims to assess contemporary practice in the treatment of severe AS across Europe and identify characteristics associated with treatment decisions, namely denial of AVR in symptomatic patients and assignment of asymptomatic patients to AVR.MethodsParticipants of the prospective, multinational IMPULSE database of patients with severe AS were grouped according to AS symptoms, and stratified into subgroups based on assignment to/denial of AVR.ResultsOf 1608 symptomatic patients, 23.8% did not undergo AVR and underwent medical treatment. Denial was independently associated with multiple factors, including severe frailty (p=0.024); mitral (p=0.002) or tricuspid (p=0.004) regurgitation grade III/IV, and the presence of renal impairment (p=0.017). Of 392 asymptomatic patients, 86.5% had no prespecified indication for AVR. Regardless, 36.3% were assigned to valve replacement. Those with an indexed aortic valve area (AVA; p=0.045) or left ventricular ejection fraction (LVEF; pConclusionsThere may be considerable discrepancies between guideline-based recommendations and clinical practice decision-making in the treatment of AS. It appears that guidelines may not fully capture the complete clinical spectrum of patients with AS. Thus, there is a need to find ways to increase their acceptance and the rate of adoption.

Arterial hypertension is one of the major health risk factors leading to coronary artery disease, stroke or peripheral artery disease. Dietary uptake of inorganic nitrite (NO2−) and nitrate (NO3−) via vegetables leads to enhanced vascular NO bioavailability and provides antihypertensive effects. The present study aims to understand the underlying vasoprotective effects of nutritional NO2− and NO3− co-therapy in mice with angiotensin-II (AT-II)-induced arterial hypertension. High-dose AT-II (1 mg/kg/d, 1w, s. c.) was used to induce arterial hypertension in male C57BL/6 mice. Additional inorganic nitrite (7.5 mg/kg/d, p. o.) or nitrate (150 mg/kg/d, p. o.) were administered via the drinking water. Blood pressure (tail-cuff method) and endothelial function (isometric tension) were determined. Oxidative stress and inflammation markers were quantified in aorta, heart, kidney and blood. Co-treatment with inorganic nitrite, but not with nitrate, normalized vascular function, oxidative stress markers and inflammatory pathways in AT-II treated mice. Of note, the highly beneficial effects of nitrite on all parameters and the less pronounced protection by nitrate, as seen by improvement of some parameters, were observed despite no significant increase in plasma nitrite levels by both therapies. Methemoglobin levels tended to be higher upon nitrite/nitrate treatment. Nutritional nitric oxide precursors represent a non-pharmacological treatment option for hypertension that could be applied to the general population (e.g. by eating certain vegetables). The more beneficial effects of inorganic nitrite may rely on superior NO bioactivation and stronger blood pressure lowering effects. Future large-scale clinical studies should investigate whether hypertension and cardiovascular outcome in general can be influenced by dietary inorganic nitrite therapy.

BackgroundContemporary data regarding the impact of comorbidities on the clinical presentation and management of patients with severe aortic stenosis (AS) are scarce.MethodsProspective registry of severe patients with AS across 23 centres in nine European countries.ResultsOf the 2171 patients, chronic kidney disease (CKD 27.3%), left ventricular ejection fraction (LVEF) ConclusionsComorbidities in severe patients with AS affect the presentation and management of patients with severe AS. TAVI was offered more often than SAVR and performed within a shorter time period.

Background Transcatheter Aortic Valve Implantation (TAVI) is today the first option for older patients with aortic valve stenosis (AS) at intermediate or high risk for surgery. Constant development of bioprosthetic valves and delivery systems have reduced complications and improved outcomes over the years. The 3rd generation Edwards Sapien 3 Valve (S3) and the 2nd generation Medtronic Evolut R Valve (ER) are currently the most frequently used worldwide. There is a paucity of published data regarding long term outcomes in these new generation TAVI patients. Methods and results In our retrospective, single-center analysis we included patients with severe Aortic Stenosis who underwent transfemoral TAVI with a new generation prosthesis between 2014 and 2016. Peri- and postprocedural outcomes of these patients were analyzed according to the VARC-2 criteria. The study population consisted of 359 patients (mean patient age 82±7 years, 47% male, mean EuroSCORE II 8.0±8). The S3 group included 215 patients, the ER group 144 patients. Median follow-up period was 3.8 years (IQR 3.3 to 4.4 years, maximum follow-up in living patients 5.1 years). Device Success rates where equal in both groups (93.0% vs. 92.4%, p=0.812). We report a 30-day mortality of 2.8% in the S3 group, 2.1% in the ER group, respectively (p=0.674). There was no difference in stroke rate, conversion to open heart surgery, major vascular complications, life-threatening or disabling bleeding or myocardial infarction. Implantation of a new permanent pacemaker was lower in the S3 group (S3: 27.4% vs. ER: 44.5%, p=0.002). While prosthesis mean gradients where higher in the S3 group (12.0 mmHg vs. 8.2 mmHg, p All-Cause Mortality up to 5 years did not show a difference between both patient groups (mean survival S3 3.5 years, ER 3.3 years, p=0.895). Independent predictors of death where impaired left ventricular function (HR 1.61, p=0.007), chronic kidney injury (HR 1.55, p=0.032), peripheral artery disease (HR 2.10, p=0.003), malignant tumor (HR 2.40, p Discussion We present a comparison of the new-generation aortic valve prostheses Edwards Sapien 3 and Medtronic Evolut R concerning long-term as well as periprocedural outcomes. The analyzed cohort consisted of patients at intermediate to high surgical risk. Yet, 30-day mortality was very low both in S3 and ER patients. Device success and periprocedural outcomes in both groups were comparable and are in line with previous studies using VARC-2 definitions. Conclusion New generation TAVI valves offer an excellent implant and outcome success rate compared to early transcatheter Aortic valve replacement. Long-term survival was independent of prostheses choice and mainly attributed to pre- and intraprocedural comorbidities and complications. All-Cause Mortality (Kaplan-Meier) Funding Acknowledgement Type of funding source: None

Background Mitral valve regurgitation (MR) is a frequent heart valve disorder affecting 1–2% of the humans in the general population and over 10% of the individuals older than 75 years. While a symptomatic and prognostic benefit of transcatheter edge-to-edge repair for MR (TMVR) was reported, data regarding long-term outcome as well as influence of concomitant tricuspid regurgitation (TR) are sparse. Purpose We aimed to investigate the impact of periinterventional development of TR on survival of patients undergoing interventional edge-to-edge repair for MR in a large retrospective monocentric study. Methods We retrospectively analyzed survival of patients successfully treated with isolated edge-to-edge repair for MR from 06/2010–03/2018 (exclusion of combined forms of TMVR) in our center. Baseline, periprocedural as well as follow-up data were gathered. Concomitant TR was evaluated at baseline and after 30 days and categorized from grades 0 (no TR) to grade III (severe TR). We analyzed the influence of severe vs. non-severe TR on 30-day, 1-year and long-term survival. Results Overall, 627 consecutive patients (47.0% female, 57.4% functional MR) were enrolled. Median follow-up time was 462 days [IQR 142–945]. Survival status was available in 96.7%. Survival rates were 97.6% at discharge, 75.7% after 1, 54.5% after 3, 37.6% after 5 and 21.7% after 7 years. TR at baseline (examination results were available in 92.3%) was categorized as severe TR in 25.6%, medium TR in 33.3%, mild TR in 35.1% and no TR in 6.0%. TR at 1 month (examination results were available in 81.1%) was severe in 16.7%, medium in 30.2%, mild in 45.6% and no TR was found in 7.4%; improvement by at least 1 TR-grade was documented in 33.6% of the patients. While a severe (compared to non-severe) TR at baseline did not affect the 30-day mortality (7.4% vs. 5.2%, p=0.354), 1-year survival was substantially impaired in those patients (36.5% vs. 23.0%, p=0.012). Accordingly, severe TR was not associated with 30d-mortality (as evaluated by univariate Cox regression, p=0.340), but with 1-year survival (HR 1.78, 95% CI 1.19–2.65, p=0.005) and showed a trend towards impaired long-term survival (HR 1.30, 95% CI 0.96–1.76, p=0.089). While residual severe TR at one month did not influence 1-year-mortality significantly (p=0.478), improvement of TR demonstrated a trend to better survival after the first year (86.9 vs. 81.0%, p=0.208) confirmed in the Cox regression analysis (HR 0.66, 95% CI 0.36–1.22, p=0.188). Conclusions In this large retrospective monocentric study with a long-term follow-up-period of >7 years after edge-to-edge therapy for MR, we demonstrated that severe TR at the time of the intervention had an impact on 1-year-survival. Furthermore, a missing periinterventional improvement of TR was shown to be unfavorable regarding the long-term survival of these patients. Funding Acknowledgement Type of funding source: None

BackgroundAn investigation into differences in the management and treatment of severe aortic stenosis (AS) between Germany, France and the UK may allow benchmarking of the different healthcare systems and identification of levers for improvement.MethodsPatients with a diagnosis of severe AS under management at centres within the IMPULSE and IMPULSE enhanced registries were eligible.ResultsData were collected from 2052 patients (795 Germany; 542 France; 715 UK). Patients in Germany were older (79.8 years), often symptomatic (89.5%) and female (49.8%) and had a lower EF (53.8%) than patients in France and UK. Comorbidities were more common and they had a higher mean Euroscore II.Aortic valve replacement (AVR) was planned within 3 months in 70.2%. This was higher (pFrance> UK; pSymptomatic patients were scheduled for an AVR in 79.4% (Germany> France> UK; pConclusionPatients in Germany had more advanced disease. The rate of intervention within 3 months after diagnosis was startlingly low in the UK. Asymptomatic patients without a formal indication often underwent an intervention in Germany and France.

Aims Several approaches for transcatheter mitral valve repair for functional mitral valve regurgitation are established. Interventional direct annuloplasty is a novel trans‐venous, trans‐septal approach. While feasibility was proven recently, knowledge on its influence on cardiac dimensions, pressures, biomarkers, and clinical outcomes is sparse. Methods and results Patients consecutively treated with direct annuloplasty‐only procedures between December 2015 and April 2018 were included in this monocentric analysis. Echocardiographic measurements, biomarker levels, clinical status [New York Heart Association (NYHA) class and 6 min walk test] were assessed at baseline, at discharge, and at a 30 day follow‐up. Overall, 18 patients (in mean 77.0 ± 7.4 years, 44.4% women) with initially all high‐grade mitral valve regurgitation (MR) were included in this study. Procedural success rate was high (94.4%) without severe complications. Direct annuloplasty resulted in MR‐reduction (post‐procedural‐MR mild or no/trace: 72.2%) and the proportion of patients with severe dyspnoea (NYHA III/IV) was reduced (88.9% vs. 50%, P = 0.008). Clinical results were associated with a relevant diminution of left atrial volumes (−16.5%, P

Objectives Transcatheter mitral valve repair (TMVR) by edge-to-edge therapy is an established treatment for severe mitral valve regurgitation (MR). Background Symptomatic and prognostic benefit in functional MR has been shown recently; nevertheless, data on long-term outcomes are sparse. Methods and results We analyzed survival of patients treated with isolated edge-to-edge repair from June 2010 to March 2018 (primarily combined edge-to-edge repair with other mitral valve interventions was excluded) in a retrospective monocentric study. Overall, 627 consecutive patients (47.0% females, 78.6 years in mean) were included. Leading etiology was functional MR (57.4%). Follow-up regarding survival was available in 97.0%. While 97.6% were discharged alive, 75.7% were alive after a 1-year, 54.5% after 3-year, 37.6% after 5-year and 21.7% after 7-year follow-up. Higher logistic Euroscores and comorbidities such as COPD and renal insufficiency were associated with higher in-hospital and 1-year mortality. Importantly, in-hospital survival increased over the years. Conclusions With the present study we established high survival rates at discharge and after 1 year of patients treated with TMVR. This goes along with high implantation numbers, increased interventional experience and a better in-hospital survival over the years. Long-term mortality in turn was substantially influenced by comorbidities.

Objectives Several interventional approaches have been established for the treatment of severe mitral regurgitation (MR) in patients at elevated risk for surgery. Direct annuloplasty is a relatively novel option in transcatheter mitral valve repair dedicated to reverse pathology in specific subsets of MR. With regard to echocardiographic guidance, this procedure presents with higher efforts in comparison with edge-to-edge therapy to enable safe and exact positioning of the device's anchors; evidence on optimal peri-interventional imaging is sparse. We tested a specific 3D-echo-guidance protocol implementing single-beat multiplanar reconstruction (MPR) and evaluated its feasibility. Methods Overall, 16 patients consecutively treated with transcatheter direct annuloplasty for severe MR (87.5% functional/6.3% degenerative/6.3% mixed pathology) were entered in this monocentric analysis. Of these, two patients received a combined procedure including edge-to-edge repair. For all implantations, a 3D-echo-guidance protocol inheriting MPR was employed. Results Periprocedural device time decreased continuously (overall mean 140 ± 55.1 minutes, 213 ± 38 minutes in the first 4 vs 108 ± 33 minutes in the last 4 procedures, P = .018) using the MPR-based echo protocol, going along with reduced fluoroscopy times and doses. Technical success rate was high (93.8%) without any serious cardiac-related adverse events. MR could be relevantly improved. Conclusion Echocardiographic guidance of transcatheter direct annuloplasty using a real time MPR-based protocol is feasible and safe. Optimized imaging might enable reduced implantation times and potentially increases safety.

Objective We evaluated percutaneous penetration of topical testosterone and subsequent transfer to subcutaneous tissue, blood and saliva. Methods This microdialysis trial involved eight healthy male volunteers. Five participants received a single dose of 50 mg testosterone gel on the abdominal skin and three untreated participants served as controls. Two microdialysis probes were inserted percutaneously into the abdominal subcutaneous adipose tissue. On the skin above one probe, testosterone gel was applied (ipsilateral side). A second control probe was inserted on the contralateral side. For the determination of total and free testosterone, samples of subcutaneous microdialysate, serum, and saliva were collected over six hours, frozen, and analysed using ELISA procedures. Results Testosterone values in the ipsilateral microdialysate of treated subjects increased significantly within 6 h after gel application compared to controls. Salivary testosterone levels showed a rapid increase within 20 min after transdermal application followed by a plateau phase with tenfold increased testosterone levels. Microdialysate testosterone of the contralateral site started to rise moderately within the normal range 1 h after administration of testosterone gel whereas total and free testosterone serum concentrations increased within 2 h in each case followed by a plateau phase. Summary and Conclusion Single topical administration of testosterone gel leads to a continuous increase of testosterone in the subcutaneous ipsilateral microdialysate. Rapid salivary testosterone increase happens after gel administration followed by tenfold increased testosterone plateau values. Despite continuous influx, testosterone concentrations in serum, saliva, and contralateral microdialysate show a plateau formation thus avoiding testosterone excess.

Objectives The influence of food intake on behavioural disorders was already described in the early 20th century. Elimination of individually allergenic food items from individual diets [“oligoantigenic diet” (OD)] showed promise to improve attention-deficit/hyperactivity disorder (ADHD) symptoms. However, only few of the positive results were evaluated by blinded symptom rating. Therefore the present study’s purpose was to evaluate the reliability of a non-blinded rating of the ADHD Rating Scale IV (ARS) for the assessment of OD effects in comparison to a blinded rating of the ARS based on pseudonymized video recordings. Methods Ten children (8m/2f) aged 8 to 14 with ADHD according to ICD-10 participated in an uncontrolled, open-label dietary intervention study. Food items, commonly related to intolerances, were eliminated for four weeks. Participants with > 40% improvement in the ARS between T1 (before the diet) and T2 (after the diet) were defined as responders. Nutrients with individual relevance to ADHD symptoms were identified in a following reintroduction phase (T3–T4) lasting 8–16 weeks. The ARS was completed by a non-blinded child and adolescent psychiatrist (T0-T4). Sessions were recorded on video, pseudonymized, and evaluated by three blinded raters. Complete data were captured for eight children. The inter-rater reliability between the non-blinded therapist and every blinded rater was determined by the intra-class correlation coefficient (ICC). Correlations according to Pearson and Spearman between the non-blinded and blinded rating were calculated for each rater. Results Two blinded raters and the non-blinded rater considered 5 of 8 (62.5%) children as responders, whereas one blinded rater disagreed as to the success of one case thus considering only 4 of 8 children as responders to the diet. Inter-rater reliability was assessed after each rater having scored 33 videos: The intra-class coefficients were >.9 for all raters (rater 1: ICC=.997, rater 2: ICC=.996, rater 3: ICC=.996) and the Spearman rho between the raters were high (n=33; rater 1: rho =.989, p

Aims Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.