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Aims Left atrial appendage closure is a non-pharmacological alternative for stroke prevention in high-risk patients with nonvalvular atrial fibrillation. The objective of the multicentre EWOLUTION registry was to obtain clinical data on procedural success and complications, and long-term patient outcomes, including bleeding and incidence of stroke/ transient ischaemic attack (TIA). Here, we report on the peri-procedural outcomes of up to 30 days. Methods and results Baseline/implant data are available for 1021 subjects. Subjects in the study were at high risk of stroke (average CHADS2 score: 2.8±1.3, CHA2DS2-VASc: 4.5±1.6) and moderate-to-high risk of bleeding (average HAS-BLED score: 2.3±1.2). Almost half of the subjects (45.4%) had a history of TIA, ischaemic stroke, or haemorrhagic stroke; 62% of patients were deemed unsuitable for novel oral anticoagulant by their physician. The device was successfully deployed in 98.5% of patients with no flow or minimal residual flow achieved in 99.3% of implanted patients. Twenty-eight subjects experienced 31 serious adverse events (SAEs) within 1 day of the procedure. The overall 30-day mortality rate was 0.7%. The most common SAE occurring within 30 days of the procedure was major bleeding requiring transfusion. Incidence of SAEs within 30 days was significantly lower for subjects deemed to be ineligible for oral anticoagulation therapy (OAT) compared with those eligible for OAT (6.5 vs. 10.2%, P = 0.042). Conclusion Left atrial appendage closure with theWATCHMAN device has a high success rate in complete LAAC with low periprocedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities. Improvement in implantation techniques has led to a reduction of peri-procedural complications previously limiting the net clinical benefit of the procedure. [ABSTRACT FROM AUTHOR]

Aims: Low-dose epoetin-β improved neo-angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date.Methods and Results: We performed a randomized, placebo-controlled, double-blind, single-centre study of 35 IU/kg body weight epoetin-β given subcutaneously once weekly for 6 months started within 3 weeks after successful percutaneous coronary intervention (PCI). Patients were included if they presented with a lesion within the proximal segment of the left anterior descending artery, the right coronary artery, or circumflex and had symptomatic heart failure. Patients with ST-segment elevation due to an acute myocardial infarct were excluded. The outcome variables were measured at baseline and at 6 months. Primary outcome measure was individual change in ejection fraction; secondary outcome was safety, change in N-terminal pro-brain natriuretic peptide, and peak VO(2). Twenty-four patients completed the 6-month treatment course. No adverse event related to the treatment occurred. Low-dose epoetin-β following PCI significantly improved global ejection fraction as measured by echocardiography (EPO: ΔEF 5.2 ± 2.0%, P= 0.013; placebo: ΔEF 0.3 ± 1.6%, P= 0.851; P= 0.019 for the inter-group difference) and cardiac magnetic resonance (EPO: ΔEF 3.1 ± 1.6%, P= 0.124; placebo: -1.9 ± 1.2%, P= 0.167; P= 0.042 for the inter-group difference). N-terminal pro-brain natriuretic peptide levels decreased in both groups without significant inter-group differences. Peak VO(2) levels increased significantly by 3.9 ± 1.1% (P< 0.05) in the EPO group, whereas in the placebo group the increase did not reach statistical significance (Δpeak VO(2) 3.0 ± 1.6, P = ns). No significant difference regarding peak VO(2) was observed between the EPO and placebo groups.Conclusions: Low-dose epoetin-β treatment following PCI is safe and feasible, and has possible beneficial effects on global ejection fraction and measures of exercise capacity. Extended low-dose epoetin-β treatment warrants further mechanistic studies as well as larger clinical trials.Clinical Trial Registration Information: NCT00568542. [ABSTRACT FROM AUTHOR]

Prostaglandin (PG) E2 release is induced in pulmonary A549 cells by the NF-κB-activating stimuli interleukin-1β (IL-1β) and phorbol 12-myristate 13-acetate (PMA). Adenoviral over-expression of IκBαΔN, a dominant NF-κB inhibitor, prevents NF-κB-dependent transcription and was used to qualify the role of NF-κB in the release of PGE2. IκBαΔN repressed IL-1β-induced, but not PMA-induced, cycloxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) expression. These data conclusively demonstrate a substantial role for NF-κB in the co-ordinate induction of COX-2, mPGES and in the corresponding release of PGE2 by IL-1β. However, other pathways are primarily responsible for PGE2 release induced by PMA. [Copyright &y& Elsevier]

The authors comment on a study which identified myofibrillogenesis regulator-1 (MR-1) as binding partner of the M-band proteins myosin regulatory light chain, myomesin and β-enolase. They note that the study supports observations that MR-1 is upregulated in a rat model of pathological cardiac hypertrophy secondary to angiotensin II infusion or abdominal aortic banding. They state that such an observation was related to an exaggerated increase in classical hypertrophy marker gene expression.

Characterizes the signal pathways activated in isolated cardiomyocytes subjected to hypoxia/reoxygenation in relation to protein synthesis focusing on reactive oxygen species, β-adrenoreceptors, P13 kinases and downstream transcription factors. Link between hypoxia/reoxygenation and cardiomyocyte hypertrophy; Analysis of the DNA binding activity of transcription factors; Clinical significance of hypoxia.

Aims: Sufficient survival time following left atrial appendage occlusion (LAAO) is essential for ensuring the efficacy and cost-effectiveness of this strategy for stroke prevention. Understanding prognostic factors for early mortality after LAAO could optimize patient selection. In the current study, we perform an in-depth analysis of 2-year mortality after LAAO, focusing particularly on potential predictors., Methods and Results: The EWOLUTION registry is a real-world cohort comprising 1020 patients that underwent LAAO. Endpoint definitions were pre-specified, and death was categorized as cardiovascular, non-cardiovascular, or unknown origin. Mortality rates were calculated from Kaplan-Meier estimates. Baseline characteristics significantly associated with death in univariate Cox regression analysis were incorporated into the multivariate analysis. All multivariate predictors were included in a risk model. Two-year mortality rate was 16.4% [confidence interval (CI): 14.0-18.7%], with 50% of patients dying from a non-cardiovascular cause. Multivariate baseline predictors of 2-year mortality included age [hazard ratio (HR) 1.05, CI: 1.03-1.08, per year increase], heart failure (HR 1.73, CI: 1.24-2.41), vascular disease (HR 1.47, CI: 1.05-2.05), valvular disease (HR 1.63, CI: 1.15-2.33), abnormal liver function (HR 1.80, CI: 1.02-3.17), and abnormal renal function (HR 1.58, CI: 1.10-2.27). Mortality rate exhibited a gradual rise as the number of risk factors increased, reaching 46.1% in patients presenting with five or six risk factors., Conclusion: One in six patients died within 2 years after LAAO. We identified six independent predictors of mortality. When combined, this model showed a gradual increase in mortality rate with a growing number of risk factors, which may guide appropriate patient selection for LAAO., Clinical Trial Registration: The original EWOLUTION registry was registered at clinicaltrials.gov under identifier NCT01972282., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Atrioventricular (AV) conduction disturbances are still common following transcatheter aortic valve replacement (TAVR). The study evaluates the feasibility and clinical effect of self-expanding (SE)-TAVR employing an optimized cusp-overlay technique (COT) at 1 year in a German all-comers population., Methods: We analyzed 1-year clinical outcomes in patients who received a SE valve employing the optimized COT. Consecutive patients who underwent SE-TAVR (EvolutR, EvolutPRO) after introduction of the COT as the default implantation technique in 2020 were included (n = 101). Consecutive TAVR patients from the same operators using the conventional implantation technique (CIT) served as the control group (n = 116)., Results: The COT was successfully performed in more than 80% of the patients in the COT group. (81.2%, n = 82/101). At discharge, no difference regarding AV block of at least II (CIT 19.47% vs COT 21%; P = .86) and permanent pacemaker (PPM) implantation (CIT 17.5% vs COT 19%; P = .73) was observed between the cohorts. New left bundle branch block (LBBB) was significantly less frequent in the COT group (CIT 40.71% vs COT 26%; P = .029). Paravalvular leakage (PVL) greater than I° was reduced in the COT cohort (CIT 8.62% vs COT 0.99%; P = .012). There was no significant difference in mortality (CIT 18.27% vs COT 13.83%; P = .44), stroke (CIT 9.62% vs COT 15.96%; P = .16) or cardiovascular rehospitalization after 1 year (CIT 25.96% vs 24.47%; P = .92) between the groups., Conclusions: Implementation of COT-TAVR was feasible and safe, and it resulted in an improvement of TAVR outcomes regarding PVL greater than I° and new onset LBBB. However, with respect to PPM, no difference was observed 1-year post-TAVR.

Aims: Evidence regarding post-procedural antithrombotic regimen other than used in randomized trials assessing percutaneous left atrial appendage (LAA) closure is limited. The present work aimed to compare different antithrombotic strategies applied in the real-world EWOLUTION study., Methods and Results: A total of 998 patients with successful WATCHMAN implantation were available for the present analysis. The composite ischaemic endpoint of stroke, transitory ischaemic attack, systemic embolism and device thrombus, and the bleeding endpoint defined as at least major bleeding were assessed during an initial period (from implant until first medication change) and long-term period (from first change up to 2 years). The antithrombotic medication chosen in the initial phase was dual antiplatelet therapy (DAPT) in 60%, oral anticoagulation (OAC) in 27%, single antiplatelet therapy (SAPT) in 7%, and no medication in 6%. In the second long-term phase, SAPT was used in 65%, DAPT in 23%, no therapy in 8%, and OAC in 4%. No significant differences were found between the groups regarding the ischaemic endpoint both in the initial period (Kaplan-Meier estimated rate 2.9% for DAPT vs. 4.3% for OAC vs. 3.9% for SAPT or no therapy) and in the second period (4.2% for SAPT vs. 1.8% for DAPT vs. 3.5% for no therapy). With respect to bleeding events, the only difference was found in the initial phase with a higher incidence in patients under SAPT or no therapy., Conclusions: Tailored antithrombotic treatment using even very reduced strategies such as SAPT or no therapy showed no significant differences regarding ischaemic complications after LAA closure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short-term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH)., Methods and Results: Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta-analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post-IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta-analysis Global Group in Chronic Heart Failure score-predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD-treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan-Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload-corrected exercise pulmonary capillary wedge pressure at the 6 months post-IASD study were associated with HFH., Conclusions: The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large-scale ongoing randomized studies are required to confirm the potential benefit of this therapy., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: While LAA closure has recently been incorporated into both European and US guidelines for stroke prevention, uncertainties regarding post-procedural drug therapy so far limit its adoption. The aim of this analysis is to compare real-world outcome data stratified for the post-procedural drug regimen employed., Methods and Results: One thousand and five patients were implanted with a WATCHMAN device in the prospective EWOLUTION study at 47 centres; 73.5% of the patients were deemed contraindicated for long-term OAC therapy. Here we report on three-month data including the first follow-up TOE exam for 94% of the study population. Following LAA closure, patients received DAPT, VKA, NOAC, single antiplatelet or no therapy (60.3%, 15.4%, 10.9%, 7% and 6.5%, respectively). Device thrombus (2.6%), stroke (0.4%) and major bleeding SAE (2.6%) rates were low overall and did not vary by post-implantation medication strategy. Patients on NOAC had the lowest bleeding rate, without an increase in device thrombus or stroke rates., Conclusions: LAA closure with the WATCHMAN device is feasible in patients with a relative or absolute contraindication to oral anticoagulation. Neither DAPT nor NOAC therapy leads to a significant increase in device thrombus, stroke or bleeding compared to the standard VKA regimen. Numerically, NOAC therapy had the lowest event rate.

Aims: Correct sizing of the ostium is a crucial step in left atrial appendage (LAA) occlusion procedures. However, unfavorable anatomy of the ostium often complicates the assessment of the true ostium diameter. We hypothesized that area-derived diameter (ADD) and perimeter-derived diameter (PDD) from three-dimensional transesophageal echocardiogram (3D-TEE) can facilitate this step of the procedure as compared with two-dimensional (2D) measurements., Methods and Results: For 55 patients within the ALSTER-LAA registry, retrospective analysis of PDD and ADD was correlated with 2D measurements used during the procedure to ascertain correct size of the Watchman device (Boston Scientific). The observed data were put into relation to the calculated area of the device with 10%-30% compression and the clinical outcome after 30 days. 3D area and perimeter measurements of the LAA ostium matched the calculated range of the different device sizes. Recapture during implantation, gaps <5 mm, and device size changes were more often observed when ADDs would also have suggested the use of a larger device., Conclusion: 3D ADDs and PDDs are feasible to use in device size decisions. Employing these measurements may allow operators to further reduce intraprocedural recapture maneuvers, peridevice leakage, and device size changes.

Aims: We have previously shown that cardiac-specific inhibition of NF-kappaB attenuates angiotensin II (AngII)-induced left ventricular (LV) hypertrophy in vivo. We now tested whether NF-kappaB inhibition is able to block LV remodelling upon chronic pressure overload and chronic AngII stimulation., Methods and Results: Cardiac-restricted NF-kappaB inhibition was achieved by expression of a stabilized IkappaBalpha mutant (IkappaBalphaDeltaN) in cells with an active alpha-myosin heavy chain (alphaMHC) promoter employing the Cre/lox technique. Upon low-gradient trans-aortic constriction (TAC, gradient 21 +/- 3 mmHg), hypertrophy was induced in both male and female control mice after 4 weeks. At this time, LV hypertrophy was blocked in transgenic (TG) male but not female mice with NF-kappaB inhibition. Amelioration of LV hypertrophy was associated with activation of NF-kappaB by dihydrotestosterone in isolated neonatal cardiomyocytes. LV remodelling was not attenuated by NF-kappaB inhibition after 8 weeks TAC, demonstrated by decreased fractional shortening (FS) in both control and TG mice irrespective of gender. Similar results were obtained when TAC was performed with higher gradients (48 +/- 4 mmHg). In TG mice, FS dropped to similar low levels over the same time course [FS sham, 29 +/- 1% (mean +/- SEM); FS control + 14 days TAC, 13 +/- 3%; FS TG + 14 days TAC, 9 +/- 5%]. Similarly, LV remodelling was accelerated by NF-kappaB inhibition in an AngII-dependent genetic heart failure model (AT1-R(alphaMHC)) associated with significantly increased cardiac fibrosis in double AT1-R(alphaMHC)/TG mice., Conclusion: NF-kappaB inhibition attenuates cardiac hypertrophy in a gender-specific manner but does not alter the course of stress-induced LV remodelling, indicating NF-kappaB to be required for adaptive cardiac hypertrophy.

We analyzed the effect of conditional, alphaMHC-dependent genetic beta-catenin depletion and stabilization on cardiac remodeling following experimental infarct. beta-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: CT(Deltaex3-6): 24 +/- 1.9%; beta-cat(Deltaex3-6): 30.2 +/- 1.6%, P < 0.001). beta-Catenin stabilization had opposite effects. No significant changes in adult cardiomyocyte survival or hypertrophy were observed in either transgenic line. Associated with the functional improvement, LV scar cellularity was altered: beta-catenin-depleted mice showed a marked subendocardial and subepicardial layer of small cTnT(pos) cardiomyocytes associated with increased expression of cardiac lineage markers Tbx5 and GATA4. Using a Cre-dependent lacZ reporter gene, we identified a noncardiomyocyte cell population affected by alphaMHC-driven gene recombination localized to these tissue compartments at baseline. These cells were found to be cardiac progenitor cells since they coexpressed markers of proliferation (Ki67) and the cardiomyocyte lineage (alphaMHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-kit(pos) and stem cell antigen-1 (Sca-1)(pos) precursor cell population but not with the Islet-1(pos) precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-1(pos) cardiac precursor cells from beta-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward alpha-actin(pos) and cTnT(pos) cardiomyocytes after 10 days (CT(Deltaex3-6): 38.0 +/- 1.0% alpha-actin(pos); beta-cat(Deltaex3-6): 49.9 +/- 2.4% alpha-actin(pos), P < 0.001). We conclude that beta-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4(pos)/Sca-1(pos) resident cardiac progenitor cells.

The armadillo-related protein beta-catenin has multiple functions in cardiac tissue homeostasis: stabilization of beta-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell-cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of beta-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible alphaMHC-CrePR1 transgene was used to induce beta-catenin depletion (loxP-flanked exons 3 to 6, beta-cat(Deltaex3-6) mice) or stabilization (loxP-flanked exon 3, beta-cat(Deltaex3) mice). Levels of beta-catenin were altered both in membrane and nuclear extracts. Analysis of the beta-catenin target genes Axin2 and Tcf-4 confirmed increased beta-catenin-dependent transcription in beta-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. beta-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with beta-catenin depletion. In contrast, mice with stabilized beta-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing beta-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in beta-catenin-stabilized mice. These data suggest that beta-catenin downregulation is required for adaptive cardiac hypertrophy.

Release of granulocyte macrophage-colony-stimulating factor (GM-CSF) from T cells is important in the differentiation, maturation, and survival of inflammatory cells. Here the induction of GM-CSF expression from T cells was dependent on transcription and translation and was prevented by dexamethasone. In primary human CD3(+) T cells, up to 3.3 kb of human GM-CSF promoter was strongly activated by PMA + PHA. Mutations in either the -85/-76 nuclear factor (NF)-kappaB site or the activator protein-1 region in the -54/-31 conserved lymphokine element 0 (CLE0) site substantially reduced promoter activity. Both GM-CSF promoter and NF-kappaB-dependent constructs were unresponsive to dexamethasone whereas the release of GM-CSF was potently repressed. Analysis of GM-CSF mRNA and protein expression at various time points and the effect of adding dexamethasone after the stimulus revealed the existence of potent mechanisms of inhibition acting at a translational level. The expression of tristetraproline and HuR, proteins that bind the AU-rich element in the GM-CSF 3'-untranslated region was unaffected by dexamethasone and overall AU-rich element binding activity was unaltered. Taken together our data support an important role for the NF-kappaB and CLE0 sites in the transcriptional control of GM-CSF expression in primary human T cells and suggest that post-transcriptional/translational mechanisms are key mediators of glucocorticoid-dependent repression.

Prostaglandin (PG) E2 release is induced in pulmonary A549 cells by the NF-kappaB-activating stimuli interleukin-1beta (IL-1beta) and phorbol 12-myristate 13-acetate (PMA). Adenoviral over-expression of IkappaBalphaDeltaN, a dominant NF-kappaB inhibitor, prevents NF-kappaB-dependent transcription and was used to qualify the role of NF-kappaB in the release of PGE2. IkappaBalphaDeltaN repressed IL-1beta-induced, but not PMA-induced, cycloxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) expression. These data conclusively demonstrate a substantial role for NF-kappaB in the co-ordinate induction of COX-2, mPGES and in the corresponding release of PGE2 by IL-1beta. However, other pathways are primarily responsible for PGE2 release induced by PMA.