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Study Question: How does a single dose of mifepristone on Day 2 after the LH peak (LH + 2) affect the endometrial receptivity transcriptome as assessed by the receptive signature established by the endometrial receptivity analysis (ERA)?Summary Answer: A single dose of mifepristone on day LH + 2 renders the endometrium non-receptive by altering the transcriptome associated with endometrial receptivity.What Is Known Already: Mifepristone is a progesterone receptor modulator that has been shown to alter endometrial receptivity. The ERA is a computational predictor that utilizes gene expression data of 248 genes from next generation sequencing to identify endometrial receptivity status.Study Design, Size, Duration: Endometrial biopsies were collected on day LH + 7 from controls (n = 11) and from women treated with mifepristone (n = 7). For further comparative analysis, samples were also obtained from women in the proliferative phase (n = 7).Participants/materials, Setting, Methods: Mifepristone treatment consisted of 200 mg administered on day LH + 2. Endometrial biopsies were treated for RNA isolation and cDNA conversion and sequencing. Endometrial receptivity status was assessed by the ERA computational predictor. Differential gene expression between groups was also assessed. Ingenuity Pathway Analysis was used for network analysis. Validation of gene expression results was done by qPCR.Main Results and the Role Of Chance: Control samples were all staged around 'receptive' as would be clinically expected for LH + 7. Treatment samples were all staged as non-receptive (all but one was classified as 'proliferative' and the last as 'pre-receptive'). Differential gene expression analysis yielded 60 differentially expressed genes between the control and treatment groups. Bioinformatic pathway analysis for differential expression showed inactivation of the progesterone and glucocorticoid receptors, consistent with mifepristone action.Limitations, Reasons For Caution: The primary limitations are the relative small number of subjects and the use of a limited gene panel.Wider Implications Of the Findings: This study sheds further light on the endometrial receptivity altering effects of mifepristone and on progesterone action. It further shows the capacity of the ERA to identify pharmacologically induced non-receptive endometrium, which expands its possible use clinically and in research.Study Funding/competing Interest(s): C.v.G. and N.R.B. have no conflicts of interest. P.G.L. reports honorarium from University of HK/Shenzhen, other from NIF, India, outside the submitted work. K.G.D. reports consultancy for Bayer AG, Exelgyn, HRA-Pharma, Gedeon Richter, MSD, Mithra, Exeltis and Natural cycles, payment for lectures from Bayer AG, NSD, Ferring, HRA-Pharma, Exelgyn and Exeltis and clinical trials for Bayer AG, MSD, Exeltis, Mithra, HRA-Pharma and Sun Pharma. C.S. has a patent gene expression profile (ERA) issued to Igenomix and is scientific director of Igenomix S.L. M.R., R.N. and J.M.V. are employees of Igenomix S.L.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Mid-term comparative data for the self-expanding ACURATE neo2 transcatheter heart valve and the balloon-expandable SAPIEN 3 Ultra are lacking., Objectives: The aim of this study was to compare 1-year outcomes after transcatheter aortic valve replacement of these 2 valves., Methods: A total of 2,106 patients from 3 centers (neo2, n = 1,166; Ultra, n = 940) undergoing transfemoral transcatheter aortic valve replacement were analyzed retrospectively. The primary endpoint was the composite of all-cause mortality, stroke, and rehospitalization at 1 year. Secondary endpoints were the individual components of the primary endpoint at 1 year. To adjust for baseline differences, nearest neighbor propensity score matching was used., Results: After matching (702 pairs), baseline characteristics were similar between groups. Device success was more common in the neo2 group (87.5% vs 82.3%; P = 0.007), irrespective of matching. DP mean after the procedure was higher for Ultra (13 mm Hg [Q1-Q3: 10-15 mm Hg] vs 8 mm Hg [Q1-Q3: 6-11] mm Hg; P < 0.001). Rates of paravalvular leakage, device embolization, and multiple valve implantations were more common in the neo2 arm, whereas major cardiac structural complications and major vascular complications occurred more frequently in the Ultra group. All other in-hospital complication rates were similar between the 2 groups. At 1 year, the cumulative incidence of the primary endpoint (14.1% for neo2 vs 14.5% for Ultra; P = 0.819) was similar between the groups. Likewise, the individual components showed no difference between the groups., Conclusions: Despite differing immediate results, the outcomes at 1 year, including the composite of all-cause mortality, stroke, or hospitalization, were similar for neo2 and Ultra transcatheter heart valves., Competing Interests: Funding Support and Author Disclosures Dr Kim has received proctor and/or speaker and/or advisory honoraria from Abbott, Boston Scientific, Edwards Lifesciences, Meril Life Sciences, Shockwave, and HID Imaging. Dr Choi has received speaker and proctor fees from Edwards Lifesciences, CytoSorbents, and Getinge. Dr Charitos is a proctor for Boston Scientific. Dr Rheude has received lecture fees from Abbott, AstraZeneca, SIS Medical, and Translumina; and has received travel support from Boston Scientific and Eli Lilly (not related to the present work). Dr Joner has received lecture fees and research grants from Edwards Lifesciences and Boston Scientific; and is a consultant for Biotronik and OrbusNeich. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : Precise implantation could play a crucial role in the technical success of transcatheter aortic valve replacement (TAVR) for some prostheses. The impact of an accidental implantation depth (ID) outside the recommended range has not been assessed for the ACURATE neo2 (NEO2). Methods : Data from 1839 patients with severe native aortic stenosis treated with the NEO2 prosthesis were evaluated. We compared the results of prostheses implanted in an ID both inside and outside the recommendations. The outcome assessment followed the Valve Academic Research Consortium-3 criteria. Results : Patients were retrospectively divided into high (<3 mm; n = 412), optimal (3-7 mm; n = 1236), and low (>7 mm; n = 169) implantations. Technical success (94.7% vs. 94.7% vs. 91.7%, p = 0.296) and device success were high (90.1% vs. 89.3% vs. 84.6%, p = 0.112) without differences between groups. Rates of relevant paravalvular regurgitation (PVL; >mild or VinV due to PVL) were comparable (1.2% vs. 1.8% vs. 1.2%, p = 0.759). Even when hemodynamics were superior in the high-implantation group, with greater iEOA (1.01 cm 2 /m 2 vs. 0.95 cm 2 /m 2 vs. 0.92 cm 2 /m 2 , p < 0.001), spontaneous embolization or after post-dilatation was more common. Low implantation was associated with a higher rate of associated pacemaker implantation (PPI) (6.1% vs. 8.8% vs. 14.8%, p = 0.001). Conclusions : Implantation with the ACURATE neo2 showed excellent hemodynamic results, including low gradients and a small number of relevant PVL, in line with a high technical success rate that was irrespective of the ID. A favorable outcome can also be achieved in accidental low or high positions. Low implantation was associated with a higher rate of associated pacemaker implantation. Deliberately high implantation should be avoided due to the risk of embolization.

Background: Challenging anatomies and comorbidities have impact on success in transcatheter aortic valve replacement (TAVR). There is controversy whether the extent of the aortic angle (AA) has an impact on procedural outcomes. Matched comparative outcome data of new generation transcatheter heart valves (THVs) in horizontal aorta (HA) are scarce., Methods: A total of 1582 patients with severe native aortic stenosis (AS) treated with the SAPIEN3 Ultra (Ultra; n = 526) or ACURATE Neo2 (Neo2; n = 1056) THVs from January 2017 to January 2023 were analyzed. Patients with non-horizontal aortas (AA < 51.7°, n = 841) were excluded. The population was matched by 1-to-1 nearest-neighbor matching (Ultra, n = 246; Neo2, n = 246). Clinical and procedural outcome were evaluated according to VARC-3 recommendations., Results: Technical success (93.1% vs. 94.7%, p = 0.572) was high after Ultra and Neo2. Device success (80.5% vs. 89.8%, p = 0.05) was inferior with Ultra. Neo2 reveals superior hemodynamic properties with lower rate of severe prosthesis patient mismatch (12.0% vs. 3.7%, p = 0.001) and elevated gradients ( ≥ $\ge $ 20 mmHg: 11.9% vs. 1.7%, p < 0.001). Ultra showed a lower rate of relevant paravalvular regurgitation ( > $\gt $ mild paravalvular regurgitation or Valve-in-Valve due to paravalvular regurgitation: 0.0% vs. 3.7%, p = 0.004). The rate of procedural bailout maneuvers (0.8% vs. 0.4%, p = 1.000) and thirty-day all-cause mortality (1.3% vs. 2.2%, p = 0.496) was similar., Conclusion: Transfemoral TAVR in patients with severe aortic stenosis and HA, using the balloon expandable Sapien3 Ultra and self-expanding ACURATE Neo2 prosthesis, is feasible and safe. Therefore, valve selection between these platforms should be made irrespective of the aortic angle by a team experienced with both valves based on their specific advantages. Large, randomized trials in this sub-group of patients would be necessary to compare long term outcomes., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Diabetic patients with coronary artery disease may benefit from elective coronary artery bypass graft (CABG) surgery. It is unknown whether this merit is transferable to patients with acute myocardial infarction (AMI) undergoing surgery., Method: A total of 1,427 patients underwent CABG within 48 hours of being diagnosed with AMI at the current institution between 2001 and 2019. Of these patients, 206 (14.4%) had insulin-dependent diabetes mellitus (IDDM) and 148 (10.4%) had non-insulin dependent diabetes mellitus (NIDDM). Retrospective data analysis was performed., Results: Patients with NIDDM showed the highest perioperative risk profile, with a EuroScore II of 11.6 (±10.3) compared with 7.8 (±8.0) in non-diabetic patients and 8.4 (±7.8) in patients with IDDM (p<0.001). Sub-analysis demonstrated a higher proportion of non-ST-elevation myocardial infarction patients in the NIDDM cohort compared with the IDDM cohort (70.9% vs 56.8%; p=0.005). Postoperatively, NIDDM patients had more sepsis (p<0.01) and longer ventilation times (p<0.001) compared with non-DM and IDDM patients (p<0.01). Wound healing complications were rare, but almost twice as high in NIDDM patients compared with non-DM and IDDM patients (4.7% vs 0.9% vs 2.4%, respectively). The 30-day mortality was highest in the NIDDM cohort (18.3% vs 11.3% vs 7.8%; p=0.012). Analysis of survival for up to 15 years revealed a significantly reduced survival of diabetic patients compared with non-diabetic patients, with lowest survival rates in NIDDM patients (p<0.001)., Conclusions: Non-insulin dependent diabetes mellitus patients undergoing CABG within 48 hours of being diagnosed with AMI are at increased risk of short-term and long-term complications. Therefore, this particular group should undergo a careful evaluation concerning the expected risks and benefits of CABG in this setting., Competing Interests: Conflict of Interest No financial support and no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/Objectives: Previous trials reported comparable results with PASCAL and earlier MitraClip generations. Limited comparative data exist for more contemporary MitraClip generations, particularly the large MitraClip XT(R/W). We aimed to evaluate acute and 30-day outcomes in patients undergoing mitral valve transcatheter edge-to-edge repair (M-TEER) with one of the large devices, either PASCAL P10 or MitraClip XT(R/W) (3rd/4th generation). Methods: A total of 309 PASCAL-treated patients were matched by propensity score to 253 MitraClip-treated patients, resulting in 200 adequately balanced pairs. Procedural, clinical, and echocardiographic outcomes were collected for up to 30 days, including subgroup analysis for mitral regurgitation (MR) etiologies. Results : PASCAL and MitraClip patients were comparable regarding age (80 vs. 79 years), sex (female: 45.5% vs. 50.5%), and MR etiology (degenerative MR: n = 94, functional MR [FMR]: n = 96, mixed MR: n = 10 in each group). Technical success rates were comparable (96.5% vs. 96.0%; p > 0.999). At discharge, the mean gradient was higher (3.3 mmHg vs. 3.0 mmHg; p = 0.038), and the residual mitral valve orifice area was smaller in MitraClip patients (3.0 cm 2 vs. 2.3 cm 2 ; p < 0.001). At discharge, the reduction to MR ≤ 2+ was comparable (92.4% vs. 87.8%; p = 0.132). However, reduction to MR ≤ 1+ was more frequently observed in PASCAL patients (67.7% vs. 56.6%; p = 0.029), driven by the FMR subgroup (74.0% vs. 60.0%; p = 0.046). No difference was observed in 30-day mortality ( p = 0.204) or reduction in NYHA-FC to ≤II ( p > 0.999). Conclusions : Both M-TEER devices exhibited high and comparable rates of technical success and MR reduction to ≤2+. PASCAL may be advantageous in achieving MR reduction to ≤1+ in patients with FMR.

Progesterone receptor antagonism is gaining attention due to progesterone's recognized role as a major mitogen in breast tissue. Limited but promising data suggest the potential efficacy of antiprogestins in breast cancer prevention. The present study presents secondary outcomes from a randomized controlled trial and examines changes in breast mRNA expression following mifepristone treatment in healthy premenopausal women. We analyzed 32 paired breast biopsies from 16 women at baseline and after two months of mifepristone treatment. In total, 27 differentially expressed genes were identified, with enriched biological functions related to extracellular matrix remodeling. Notably, the altered gene signature induced by mifepristone in vivo was rather similar to the in vitro signature. Furthermore, this gene expression signature was linked to breast carcinogenesis and notably linked with progesterone receptor expression status in breast cancer, as validated in The Cancer Genome Atlas dataset using the R2 platform. The present study is the first to explore the breast transcriptome following mifepristone treatment in normal breast tissue in vivo, enhancing the understanding of progesterone receptor antagonism and its potential protective effect against breast cancer.

Background: Comparative data on transcatheter self-expanding ACURATE neo2 (NEO2) and balloon-expandable SAPIEN 3 Ultra prostheses in technically challenging anatomy of severe aortic valve calcified aortic annuli are scarce., Methods: A total of 1987 patients with severe native aortic stenosis treated with the self-expanding NEO2 (n=1457) or balloon-expandable SAPIEN 3 Ultra (n=530) from January 2017 to April 2023 were evaluated. The primary end point was procedural outcome according to the Valve Academic Research Consortium 3 definitions. Propensity matching defined 219 pairs with severe calcification (calcium density cutoff, 758 AU/cm 2 ) of the native aortic valve., Results: Technical success (90.4% versus 91.8%; risk difference, 1.4% [95% CI, -4.4 to -7.2]; P =0.737) and device success at 30 days (80.8% versus 75.8%; risk difference, -5.0% [95% CI, -13.2 to 3.1]; P =0.246) were comparable between NEO2 and SAPIEN 3 Ultra. The rate of severe prosthesis-patient mismatch (1.1% versus 10.1%; risk difference, 10.0% [95% CI, 4.0-13.9]; P <0.001) and mean transvalvular gradient ≥20 mm Hg (2.8% versus 14.3%; risk difference, 11.5% [95% CI, 5.8-17.1]; P <0.001) was lower with NEO2. The rate of more-than-mild paravalvular leakage or valve-in-valve due to paravalvular leakage was significantly higher (6.2% versus 0.0%; risk difference, 6.2% [95% CI, -10.1 to -2.7]; P =0.002), and there was a tendency for a higher rate of device embolization or migration (1.8% versus 0.0%; risk difference, -1.8% [95% CI, -4.1 to 0.4]; P =0.123) with NEO2. Multivarate regression revealed no independent impact of transcatheter heart valve selection on device success (odds ratio, 0.93 [95% CI, 0.48-1.77]; P =0.817)., Conclusions: In patients with severely calcified annuli, supraannular implantation of NEO2 showed hemodynamic advantages. Nevertheless, NEO2 was associated with a higher incidence of relevant paravalvular leakage and a numerically higher rate of device embolization than SAPIEN 3 Ultra in this particular patient group., Competing Interests: Disclosures Dr Kim has received proctor fees and speaker honoraria from Boston Scientific, Edwards Lifesciences, Medtronic, and Abbott. Dr Möllmann has received proctor fees and speaker honoraria from Boston Scientific, Biotronik, and Abbott. Dr Blumenstein has received proctor fees and speaker honoraria from Boston Scientific and Abbott. Dr Hamm is an advisory board member of Medtronic. The other authors report no conflicts.

Competing Interests: Declaration of Competing Interest Dr. Kim reports personal fees from Abbott, Boston Scientific, Edwards Lifesciences, Meril Life Sciences, and Shockwave Medical; Dr. Blumenstein reports proctor fees from Boston Scientific; Dr. Choi reports speaker/proctor fees from Edwards Lifesciences, Cytosorbents, and Getinge; Dr. Charitos reports proctor fees from Boston Scientific; Dr. Möllmann reports proctor fees and/or speaker honoraria from Abbott, Biotronic, Edwards Lifesciences, and Boston Scientific. The remaining authors have no competing interests to declare.

Background: We previously reported procedural and 30-day outcomes of a German early multicenter experience with the PASCAL system for severe mitral regurgitation (MR). This study reports 1-year outcomes of mitral valve transcatheter edge-to-edge repair with the PASCAL system according to MR etiology in a large all-comer cohort., Methods and Results: Clinical and echocardiographic outcomes up to 1-year were investigated according to MR etiology (degenerative [DMR], functional [FMR], or mixed [MMR]) in the first 282 patients with symptomatic MR 3+/4+ treated with the PASCAL implant at 9 centers in 2019. A total of 282 patients were included (33% DMR, 50% FMR, 17% MMR). At discharge, MR reduction to ≤1+/2+ was achieved in 58%/87% of DMR, in 75%/97% of FMR, and in 78%/98% of patients with MMR ( P =0.004). MR reduction to ≤1+/2+ was sustained at 30 days (50%/83% DMR, 67%/97% FMR, 74%/100% MMR) and at 1 year (53%/78% DMR, 75%/97% FMR, 67%/91% MMR) with significant differences between etiologies. DMR patients with residual MR 3+/4+ at 1-year had at least complex valve morphology in 91.7%. Valve-related reintervention was performed in 7.4% DMR, 0.7% FMR, and 0.0% MMR ( P =0.010). At 1-year, New York Heart Association Functional Class was significantly improved irrespective of MR etiology ( P <0.001)., Conclusions: In this large all-comer cohort, mitral valve transcatheter edge-to-edge repair with the PASCAL system was associated with an acute and sustained MR reduction at 1-year in all causes. However, in patients with DMR, MR reduction was less pronounced, reflecting the high incidence of complex or very complex anatomies being referred for mitral valve transcatheter edge-to-edge repair.

Background: Third-generation transcatheter heart valves (THVs) are designed to improve outcomes. Data on the new intra-annular self-expanding NAVITOR are scarce., Aims: The aim of this analysis was to compare outcomes between the PORTICO and the NAVITOR systems., Methods: Data from 782 patients with severe native aortic stenosis treated with PORTICO ( n = 645) or NAVITOR ( n = 137) from 05/2012 to 09/2022 were evaluated. The clinical and hemodynamic outcomes of 276 patients (PORTICO, n = 139; NAVITOR, n = 137) were evaluated according to VARC-3 recommendations., Results: Rates of postprocedural more-than-mild paravalvular leakage (PVL) were significantly lower for NAVITOR than for PORTICO (7.2% vs. 1.5%, p = 0.041). In addition, severe bleeding rates (27.3% vs. 13.1%, p = 0.005) and major vascular complications (5.8% vs. 0.7%, p = 0.036) were lower in the NAVITOR group. The mean gradients (7 vs. 8 mmHg, p = 0.121) and calculated aortic valve areas (1.90 cm 2 vs. 1.99 cm 2 , p = 0.235) were comparable. Rates of PPI were similarly high in both groups (15.3 vs. 21.6, p = 0.299)., Conclusions: The NAVITOR demonstrated favorable in-hospital procedural outcome data, with lower rates of relevant PVL, major vascular complications, and severe bleeding than its predecessor the PORTICO and preserved favorable hemodynamic outcomes.