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Abstract Surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) are options in severe aortic valve stenosis (AVS). Cardiovascular (CV) and cerebrovascular (CBV) control markers, derived from variability of heart period, systolic arterial pressure, mean cerebral blood velocity and mean arterial pressure, were acquired in 19 AVS patients (age: 76.8 ± 3.1 yrs, eight males) scheduled for SAVR and in 19 AVS patients (age: 79.9 + 6.5 yrs, 11 males) scheduled for TAVI before (PRE) and after intervention (POST,

Abstract In transcatheter aortic valve implantation (TAVI), final device position may be affected by device interaction with the whole aortic landing zone (LZ) extending to ascending aorta. We investigated the impact of aortic LZ curvature and angulation on TAVI implantation depth, comparing short-frame balloon-expanding (BE) and long-frame self-expanding (SE) devices. Patients (n = 202) treated with BE or SE devices were matched based on one-to-one propensity score. Primary endpoint was the mismatch between the intended (HPre) and the final (HPost) implantation depth. LZ curvature and angulation were calculated based on the aortic centerline trajectory available from pre-TAVI computed tomography. Total LZ curvature ( $${k}_{LZ,tot}$$ k L Z , t o t ) and LZ angulation distal to aortic annulus ( $${\alpha }_{LZ,Distal}$$ α L Z , D i s t a l ) were greater in the SE compared to the BE group (P

Objective: Bleeding is frequent during transcatheter aortic valve implantation (TAVI), especially when performed through a transapical approach (TA), and is associated with a worse prognosis. The present study aims to test the implication of red blood cell (RBC) transfusion and the optimal transfusion strategy in this context. Methods: Among 11,265 participants in the multicenter TRITAVI (Transfusion Requirements in Transcatheter Aortic Valve Implantation) registry, 548 patients (4.9%) who received TA-TAVI at 19 European centers were included. One-to-one propensity score matching was performed to reduce treatment selection bias and potential confounding among transfused versus non-transfused patients. The primary endpoint of the study was the 30-day occurrence of all-cause mortality. Results: 209 patients (38 %) received RBC transfusions. The primary endpoint occurred in 47 (8.6 %) patients. Propensity score matching identified 188 pairs of patients with and without RBC transfusion. In the propensity score-matched analysis, RBC transfusion was associated with increased 30-day mortality (HR 3.35, 95 % CI 1.51 – 7.39; p = 0.002). At multivariable cox regression analysis, RBC transfusion was an independent predictor of 30-day mortality (HR 3.07, 95 % CI 1.01–9.41, p = 0.048), as well as baseline ejection fraction (HR 0.96, 95 % CI 0.92–0.99, p = 0.043), and acute kidney injury (HR 3.95, 95 % CI 1.11–14.05, p = 0.034). Conclusions: RBC transfusion is an independent predictor of short-term mortality in patients undergoing TA-TAVI, regardless of major bleeding.Clinical trial registration: https://www.clinicaltrials.gov Unique identifier: NCT03740425.

IntroductionRecent studies have shown gender differences in cardiovascular outcomes after left atrial appendage closure (LAAC), highlighting different complication rates and adverse events, particularly in short-term assessments. As a result, there remains a significant knowledge gap on how these differences directly impact the efficacy and safety of LAAC procedures. The aim of this retrospective study was to investigate the clinical outcomes of LAAC in women and men using the Watchman FLX device.MethodsThis retrospective, multicenter study analyzes gender-specific outcomes in 650 patients who underwent LAAC with the Watchman FLX device between March 2019 and May 2022, drawn from the ITALIAN-FLX registry.ResultsThe results show comparable rates of all-cause mortality, stroke, transient ischemic attack and major bleeding in men and women 12 months after the procedure. Notably, no significant gender differences were found for periprocedural complications.ConclusionIn conclusion, this study shows that LAAC with the Watchman FLX device has comparable clinical outcomes between genders at both short-term and long-term follow-up.

Background Minimally invasive mitral valve repair has a favorable risk–benefit profile in patients with significant de novo mitral regurgitation. Its role in patients with prior mitral valve repair is uncertain. We aimed to appraise the outcome of patients undergoing transcatheter edge‐to‐edge repair (TEER) with prior transcatheter or surgical mitral valve repair (SMVR). Methods and Results We queried the Italian multicenter registry on TEER with MitraClip, distinguishing naïve patients from those with prior TEER or (SMVR). Inhospital and long‐term clinical/echocardiographic outcomes were appraised. The primary outcome was the occurrence of death or rehospitalization for heart failure. A total of 2238 patients were included, with 2169 (96.9%) who were naïve to any mitral intervention, 29 (1.3%) with prior TEER, and 40 (1.8%) with prior SMVR. Several significant differences were found in baseline clinical and imaging features. Respectively, device success was obtained in 2120 (97.7%), 28 (96.6%), and 38 (95.0%, P=0.261) patients; procedural success in 2080 (95.9%), 25 (86.2%), and 38 (95.0%; P=0.047); and inhospital death in 61 (2.8%), 1 (3.5%), and no (P=0.558) patients. Clinical follow‐up after a mean of 14 months showed similar rates of death, cardiac death, rehospitalization, rehospitalization for heart failure, and their composite (all P>0.05). Propensity score–adjusted analysis confirmed unadjusted analysis, with lower procedural success for the prior TEER group (odds ratio, 0.28 [95% CI, 0.09–0.81]; P=0.019) but similar odds ratios and hazard ratios for all other outcomes in the naïve, TEER, and SMVR groups (all P>0.05). Conclusions In carefully selected patients, TEER can be performed using the MitraClip device even after prior TEER or SMVR.

Background Dialysis is a rare but serious complication after transcatheter aortic valve replacement. We analyzed the large multicenter TRITAVI (transfusion requirements in transcatheter aortic valve implantation) registry in order to develop and validate a clinical score assessing this risk. Methods and Results A total of 10 071 consecutive patients were enrolled in 19 European centers. Patients were randomly assigned (2:1) to a derivation and validation cohort. Two scores were developed, 1 including only preprocedural variables (TRITAVIpre) and 1 also including procedural variables (TRITAVIpost). In the 6714 patients of the derivation cohort (age 82±6 years, 48% men), preprocedural factors independently associated with dialysis and included in the TRITAVIpre score were male sex, diabetes, prior coronary artery bypass graft, anemia, nonfemoral access, and creatinine clearance

Abstract Anomalous aortic origin of the coronary artery (AAOCA) is a rare disease associated with sudden cardiac death, usually related to physical effort in young people. Clinical routine tests fail to assess the ischemic risk, calling for novel diagnostic approaches. To this aim, some recent studies propose to assess the coronary blood flow (CBF) in AAOCA by computational simulations but they are limited by the use of data from literature retrieved from normal subjects. To overcome this limitation and obtain a reliable assessment of CBF, we developed a fully patient-specific lumped parameter model based on clinical imaging and in-vivo data retrieved during invasive coronary functional assessment of subjects with AAOCA. In such a way, we can estimate the CBF replicating the two hemodynamic conditions in-vivo analyzed. The model can mimic the effective coronary behavior with high accuracy and could be a valuable tool to quantify CBF in AAOCA. It represents the first step required to move toward a future clinical application with the aim of improving patient care. The study was registered at Clinicaltrial.gov with (ID: NCT05159791, date 2021-12-16).

Background: The CONtrolled delivery For ImproveD outcomEs with cliNiCal Evidence registry was initiated to characterize the clinical safety and device performance from experienced transcatheter aortic valve implantation (TAVI) centers in Europe and Australia that use the Portico valve to treat patients with severe aortic stenosis. We herein report for the first time the valve performance at 30-day across all implanted valve sizes and the 1-year survival from this registry. Methods: This was a prospective, multicenter, single-arm observational clinical investigation of patients clinically indicated for implantation of a Portico valve in experienced TAVI centers. Patients were treated with a commercially available valve (size 23, 25, 27, or 29 mm) using either the first-generation delivery system (DS) (n = 501) or the second-generation (FlexNav) DS (n = 500). Adverse events were adjudicated by an independent clinical events committee according to Valve Academic Research Consortium-2 criteria. Echocardiographic outcomes were assessed at 30 days by an independent core laboratory, and a survival check was performed at 1 year. Results: We enrolled 1001 patients (82.0 years, 62.5% female, 63.7% New York Heart Association functional class III/IV at baseline) from 27 clinical sites in 8 countries across Europe and one site in Australia. Implantation of a single valve was successful in 97.5% of subjects. Valve hemodynamics at 30 days were substantially improved relative to baseline, with large aortic valve areas and low mean gradients across all implanted valve sizes (aortic valve areas were 1.7 ± 0.4, 1.7 ± 0.5, 1.8 ± 0.5, and 2.0 ± 0.5 cm2, and mean gradients were 7.0 ± 2.7, 7.5 ± 4.7, 7.3 ± 3.3, and 6.4 ± 3.3 mmHg for 23, 25, 27, and 29 mm valve sizes, respectively). Across all implanted valve sizes, most patients (77.1%) had no patient-prosthesis mismatch. Death from any cause within 1 year occurred in 13.7% of the patients in the first-generation DS group as compared with 11.0% in the second-generation DS group (p = 0.2). Conclusions: The Portico valve demonstrated excellent hemodynamic performance across all valve sizes in a large cohort of subjects implanted in experienced TAVI centers. One-year survival rates were favorable when using both the first-generation and second-generation (FlexNav) DSs in this high-risk cohort. ClinicalTrials.gov Identifier: NCT03752866.

BackgroundThird generation drug-eluting stents (DES) potentially offer better technical performance and reduced neointimal proliferation than previous generation DES. The XLIMIT non-inferiority trial evaluated the performance of the Xlimus (a novel sirolimus-eluting coronary stent system) in terms of endothelialization and tissue healing compared to the bioresorbable polymer Synergy DES.MethodsA total of 177 patients undergoing percutaneous coronary intervention (PCI) were randomized in a 2:1 ratio (2 Xlimus: 1 Synergy). The primary endpoints, defined as the in-stent neointimal volume weighted by the sum of the lengths of the implanted stent (ISNV) and the in-stent neointimal percent volume obstruction (%VO) were evaluated at 6–9 months by means of optical coherence tomography (OCT). Additional OCT parameters as well as clinical endpoints were also collected.ResultsMost of the patients were males (77.4%), and the mean age was 64 years. One third of the population had stable angina/silent ischemia. A total of 300 stents (237 lesions) were analyzed: 198 (152 lesions) were in the Xlimus group, and 102 (85 lesions) in the Synergy group. The ISNV in the Xlimus group was 30.7 ± 24.5 mm3 while in the Synergy group it was 26.5 ± 26.7 mm3: the difference between the two means was 0.08 (−0, 04–0, 45), p = 0.018, thus meeting the non-inferiority hypothesis. The %VO was 16.3% ± 10.4% and 13.3% ± 10.8% in the Xlimus and Synergy groups, respectively: the difference between the two means was 3.0 (−0, 06–4, 2), (p = 0.01), thus meeting the non-inferiority hypothesis. No difference was found with respect to the secondary OCT endpoints as well as for clinical endpoints.ConclusionsThe study results confirm that the biological interaction of the Xlimus and Synergy DES with the coronary artery is comparable, and that translates in very reassuring OCT parameters at follow-up: as such, the Xlimus is non-inferior to the Synergy.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT03745053).

Abstract Management of congenital coronary artery anomalies (CAA) is not standardized due to the variety of conditions included and their rare prevalence. Detection of CAA during myocardial infarction with non‐obstructive coronary arteries (MINOCA) may induce clinicians to address the patient for surgery as CAA is not included in any algorithm1,2 for the management of MINOCA and American Association for Thoracic Surgery evidence‐based guidelines suggest surgical repair for patients with anomalous aortic origin of a coronary artery and symptoms compatible with myocardial ischaemia.3 We present the case of a 35‐year‐old man with an anomalous origin of left coronary artery from right Valsalva sinus with pre‐pulmonic course detected during urgent coronary angiography for suspected myocardial infarction. Stress cardiac magnetic resonance did not show signs of ischaemia at high‐dose dobutamine but did reveal a recent myocarditis. This clinical case highlights the need for accurate risk stratification in CAA especially when confounding clinical scenarios co‐exist.

Background Little is known about the impact of transcatheter mitral valve edge‐to‐edge repair on changes in left ventricular ejection fraction (LVEF) and the effect of an acute reduction in LVEF on prognosis. We aimed to assess changes in LVEF after transcatheter mitral valve edge‐to‐edge repair for both primary and secondary mitral regurgitation (PMR and SMR, respectively), identify rates and predictors of LVEF reduction, and estimate its impact on prognosis. Methods and Results In this international multicenter registry, patients with both PMR and SMR undergoing transcatheter mitral valve edge‐to‐edge repair were included. We assessed rates of acute LVEF reduction (LVEFR), defined as an acute relative decrease of >15% in LVEF, its impact on all‐cause mortality, major adverse cardiac event (composite end point of all‐cause death, mitral valve surgery, and residual mitral regurgitation grade ≥2), and LVEF at 12 months, as well as predictors for LVEFR. Of 2534 patients included (727 with PMR, and 1807 with SMR), 469 (18.5%) developed LVEFR. Patients with PMR were older (79.0±9.2 versus 71.8±8.9 years; P

BackgroundThe Cocoon patent foramen ovale (PFO) Occluder is a new generation nitinol alloy double-disk device coated with nanoplatinum, likely useful in patients with nickel hypersensitivity. Early results and mid-term outcomes of this device in percutaneous PFO closure are missing.AimsTo assess the preliminary efficacy and safety profile of PFO closure with Cocoon device in an Italian multi-center registry.MethodsThis is a prospective registry of 189 consecutive adult patients treated with the Cocoon PFO Occluder at 15 Italian centers from May 2017 till May 2020. Patients were followed up for 2 years.ResultsClosure of the PFO with Cocoon Occluder was carried out successfully in all patients, with complete closure without residual shunt in 94.7% of the patients and minimal shunt in 5.3%. Except from a case of paroxysmal supraventricular tachycardia and a major vascular bleeding, no procedural and in-hospital device-related complications occurred. No patient developed cardiac erosions, allergic reactions to nickel, or any other major complications during the follow-up. During the follow-up period, 2 cases of new-onset atrial fibrillation occurred within thirty-day.ConclusionsPercutaneous closure of PFO with Cocoon Occluder provided satisfactory procedural and mid-term clinical follow-up results in a real-world registry.

Patients with non-paradoxical low-flow–low-gradient (LFLG) aortic stenosis (AS) are at increased surgical risk, and thus, they may particularly benefit from transcatheter aortic valve replacement (TAVR). However, data on this issue are still limited and based on the results with older-generation transcatheter heart valves (THVs). The aim of this study was to investigate early and mid-term outcome of TAVR with newer-generation THVs in the setting of LFLG AS. Data for the present analysis were gathered from the OBSERVANT II dataset, a national Italian observational, prospective, multicenter cohort study that enrolled 2,989 consecutive AS patients who underwent TAVR at 30 Italian centers between December 2016 and September 2018, using newer-generation THVs. Overall, 420 patients with LVEF ≤50% and mean aortic gradient

Background Acute kidney injury (AKI) after transcatheter aortic valve replacement (TAVR) is associated with increased mortality. However, it is controversial whether AKI affects prognosis per se, being linked to baseline chronic kidney disease (CKD) and bleeding complications. The aim of this study was to disentangle, applying mediation analysis, the association between AKI and clinical outcome, considering CKD and bleedings. Methods and Results Consecutive patients undergoing TAVR were prospectively enrolled at 5 high‐volume centers in Italy. AKI was defined according to Valve Academic Research Consortium‐3 consensus, whereas bleeding with Bleeding Academic Research Consortium. Primary outcome was all‐cause mortality after 1‐year follow‐up. Among 2621 patients undergoing TAVR, AKI occurrence was associated with 1‐year mortality. This association of AKI with the primary end points remained significant after adjusting for baseline risk estimators, either Society of Thoracic Surgeons score (hazard ratio [HR], 2.78 [95% CI, 1.95–3.80], P

Background: The DynamX Novolimus-Eluting Coronary Bioadaptor System (DynamX® Bioadaptor) has uncaging elements that disengage after the resorption of the polymer coating, aiming to restore vessel function in the treated segment and to avoid long-term adverse outcomes associated with the permanent caging of the coronary artery seen with conventional stenting. Methods: This prospective, multicenter, single-arm first-in-human study enrolled 50 patients in Belgium and Italy who were treated with the DynamX Bioadaptor. Eligible patients had de novo lesions in coronary arteries measuring between 2.5 and 3.5 mm in diameter and ≤24 mm in length. Clinical follow-up was performed up to 36 months. This analysis includes the intention-to-treat population and is based on data available. The preclinical studies include optical coherence tomography (OCT) analyses of 5 DynamX Bioadaptors implanted in 3 mini Yucatan pigs (at 3, 12 and 24 months), and assessment of smooth muscle cell gene expression profile in 8 pigs of which each was implanted with the DynamX Bioadaptor and the Xience drug-eluting stent. To assess the gene expression profile by quantitative real-time polymerase chain reaction, animals were sacrificed at 3, 6, 9 and 12 months. Results: Target lesion failure at 36 months was 8.7% (4/46), consisting of one clinically-driven target lesion revascularization and 3 cardiac deaths (all site-reported to be unrelated to the device or procedure). There were no additional target vessel revascularization and no definite or probable scaffold thrombosis. Preclinical data confirmed late lumen enlargement (from 7.02 ± 1.31 mm2 at baseline to 8.46 ± 1.31 mm2 at 24 months) and identified an increased expression of contractile genes around 9 months compared to a conventional drug-eluting stent. Conclusions: The DynamX Bioadaptor demonstrated very good 36-month clinical outcomes, highlighted by the absence of target-vessel myocardial infarction and definite or probable device thrombosis, and only one target lesion revascularization up to 36 months. These data are supported by preclinical studies that showed late lumen enlargement by OCT and an increased expression of contractile genes around 9 months compared to conventional drug-eluting stents, indicating faster vessel healing. Larger clinical studies are necessary to compare outcomes against contemporary drug-eluting stents. Clinical Trial Registration: https://clinicaltrials.gov/: NCT03429894.

BackgroundA severe prosthesis-patient mismatch (PPM) is associated with adverse outcomes following transcatheter aortic valve replacement (TAVR) for de novo aortic stenosis or a failed surgical bioprosthesis. The impact of severe PPM in patients undergoing TAV-in-TAVR is unknown.AimWe sought to investigate the incidence and 1-year outcomes of different grades of PPM in patients undergoing TAV-in-TAVR.Materials and methodsThe TRANSIT-PPM is an international registry, including cases of degenerated TAVR treated with a second TAVR. PPM severity, as well as in-hospital, 30-day, and 1-year outcomes were defined according to the Valve Academic Research Consortium-3 (VARC-3) criteria.ResultsAmong 28 centers, 155 patients were included. Severe PPM was found in 6.5% of patients, whereas moderate PPM was found in 14.2% of patients. The rate of severe PPM was higher in patients who underwent TAV-in-TAVR with a second supra-annular self-expanding (S-SE) TAVR (10%, p = 0.04). Specifically, the rate of severe PPM was significantly higher among cases of a SE TAVR implanted into a balloon-expandable (BE) device (19%, p = 0.003). At 1-year follow-up, the rate of all-cause mortality, and the rate of patients in the New York Heart Association (NYHA) class III/IV were significantly higher in the cohort of patients with severe PPM (p = 0.016 and p = 0.0001, respectively). Almost all the patients with a severe PPM after the first TAVR had a failed < 23 mm BE transcatheter heart valve (THV): the treatment with an S-SE resolved the severe PPM in the majority of the cases.ConclusionAfter TAV-in-TAVR, in a fifth of the cases, a moderate or severe PPM occurred. A severe PPM is associated with an increased 1-year all-cause mortality.Clinical trial registration[https://clinicaltrials.gov], identifier [NCT04500964].

Redo transcatheter aortic valve replacement (TAVR) may pose the risk of coronary flow obstruction. We report 2 cases of severe TAVR regurgitation due to different physiopathological mechanisms in which TAVR-in-TAVR could be at high risk for sinus sequestration. Both cases were successfully treated by in-series implantation of a second transcatheter heart valve, thus avoiding sinus sequestration. (Level of Difficulty: Intermediate.)

Abstract MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed‐forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT‐typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity.

Pharmacological treatment is the cornerstone therapy of heart failure with reduced ejection fraction (HFrEF). In addition, several percutaneous techniques have been developed to treat symptomatic patients, with specific heart failure (HF) phenotypes (e.g., valvular heart disease) that require non-pharmacological treatment. Given their prognostic relevance, it is imperative to deliver high-level patient care. This review provides a clinical overview on the available data regarding transcatheter devices in the armamentarium of contemporary interventional cardiologists, focusing on the clinical and anatomical selection criteria.

BackgroundPercutaneous coronary intervention (PCI) is used increasingly for revascularization of unprotected left main coronary artery (LMCA) disease. Observational studies and subgroup analyses from clinical trials, have suggested a possible benefit from the use of intravascular ultrasound (IVUS) guidance when performing unprotected LMCA PCI. However, the value of imaging with IVUS has never been proven in an appropriately powered randomized clinical trial. The OPtimizaTIon of Left MAin PCI With IntravascuLar Ultrasound (OPTIMAL) trial has been designed to establish whether IVUS-guided PCI optimization on LMCA is associated with superior clinical outcomes when compared with standard qualitative angiography-guided PCI.MethodsThe OPTIMAL trial is a randomized, multicenter, international study designed to enroll a total of 800 patients undergoing PCI for unprotected LMCA disease. Patients will be randomized in a 1:1 fashion to IVUS-guided PCI versus angiogram-guided PCI. In patients allocated to the angiogram-guided arm, use of IVUS is discouraged, unless there are safety concerns. In patients allocated to the IVUS guidance arm, pre-procedural IVUS assessment is highly recommended, whilst post-procedural IVUS assessment is mandatory to confirm appropriate stenting result and/or to guide stent result optimization, according to predefined criteria. Patients will be followed up to 2 years after the index procedure. The primary outcome measure is the Academic Research Consortium (ARC) patient-oriented composite endpoint (PoCE) which includes all-cause death, any stroke, any myocardial infarction and any repeat revascularization at 2 years follow-up.DiscussionThe OPTIMAL trial aims to provide definitive evidence about the clinical impact of IVUS-guidance during PCI to an unprotected LMCA. It is anticipated by the investigators, that an IVUS-guided strategy will be associated with less clinical events compared to a strategy guided by angiogram alone.Trial registrationClinicalTrials.gov: NCT04111770. Registered on October 1, 2019.

Background: The impact of nodular calcifications in left ventricular outlow tract (LVOT) and aortic annulus on the procedural outcome of transcatheter aortic valve implantation (TAVI) with new-generation devices is yet to be elucidated. Similarly, computational simulations may provide a novel insight into the biomechanical features of TAVI devices and their interaction with nodular calcifications. Methods: This retrospective single-center study included 232 patients submitted to TAVI with Evolut-R (53.4%), Portico (33.6%) and Lotus (13.0%) devices with available preoperative computed tomography (CT) angiography and evidence of nodular calcifications in aortic annulus and/or LVOT. Calcification severity was defined ≥moderate in presence of at least two nodules or one nodule ≤5 mm. Three virtual simulation models of aortic root presenting a nodular calcification of increasing size were implemented. Stress distribution, stent-root contact area and paravalvular orifice area were computed. Results: At least moderate calcifications were found in 123 (53.0%) patients, with no sex differences. Among the ≥moderate calcification group, lower device success rate was evident (87.8% vs. 95.4%; p = 0.039). Higher rates of ≥moderate paravalvular leak (PVL) (11.4% vs. 3.7%; p = 0.028) and vascular complications (9.8% vs. 2.8%; p = 0.030) were also observed. Among the Evolut-R group, higher rates of at ≥moderate PVL (12.1%) were observed compared to Portico (3.8%; p = 0.045) and Lotus (0.0%; p = 0.044) groups. Calcification of both annulus and LVOT (odds ratio [OR] 0.105; p = 0.023) were independent predictors of device success. On computational simulations, Portico exhibited homogeneous stress distribution by increasing calfications and overall a larger paravalvular orifice areas compared to Evolut-R and Lotus. Evolut-R showed higher values of average stress than Portico, although with a more dishomogeneous distribution leading to greater paravalvular orifice areas by severe calcifications. Lotus showed overall small paravalvular orifice areas, with no significant increase across the three models. Conclusions: At least moderate nodular calcifications in the annulus/LVOT region significantly affected TAVI outcome, as they were independent predictors of device success. Lotus and Portico seemed to perform better than Evolut-R as for device success and ≥moderate PVL. Computational simulations revealed unique biomechanical features of the investigated devices in terms of stent compliance and radial force.

Cerebral cortex projection neurons (PNs) are generated from intermediate progenitors (IPs), which are in turn derived from radial glial progenitors (RGPs). To investigate developmental processes in IPs, we profiled IP transcriptomes in embryonic mouse neocortex, using transgenic Tbr2-GFP mice, cell sorting, and microarrays. These data were used in combination with in situ hybridization to ascertain gene sets specific for IPs, RGPs, PNs, interneurons, and other neural and non-neural cell types. RGP-selective transcripts (n = 419) included molecules for Notch receptor signaling, proliferation, neural stem cell identity, apical junctions, necroptosis, hippo pathway, and NF-κB pathway. RGPs also expressed specific genes for critical interactions with meningeal and vascular cells. In contrast, IP-selective genes (n = 136) encoded molecules for activated Delta ligand presentation, epithelial-mesenchymal transition, core planar cell polarity (PCP), axon genesis, and intrinsic excitability. Interestingly, IPs expressed several “dependence receptors” (Unc5d, Dcc, Ntrk3, and Epha4) that induce apoptosis in the absence of ligand, suggesting a competitive mechanism for IPs and new PNs to detect key environmental cues or die. Overall, our results imply a novel role for IPs in the patterning of neuronal polarization, axon differentiation, and intrinsic excitability prior to mitosis. Significantly, IPs highly express Wnt-PCP, netrin, and semaphorin pathway molecules known to regulate axon polarization in other systems. In sum, IPs not only amplify neurogenesis quantitatively, but also molecularly “prime” new PNs for axogenesis, guidance, and excitability.

Secondary mitral regurgitation (MR) occurs despite structurally normal valve apparatus due to an underlying disease of the myocardium leading to disruption of the balance between tethering and closing forces with ensuing failure of leaflet coaptation. In patients with heart failure (HF) and left ventricular dysfunction, secondary MR is independently associated with poor outcome, yet prognostic benefits related to the correction of MR have remained elusive. Surgery is not recommended for the correction of secondary MR outside coronary artery bypass grafting. Percutaneous mitral valve repair (PMVR) with MitraClip implantation has recently evolved as a new transcatheter treatment option of inoperable or high-risk patients with severe MR, with promising results supporting the extension of guideline recommendations. MitraClip is highly effective in reducing secondary MR in HF patients. However, the derived clinical benefit is still controversial as two randomized trials directly comparing PMVR vs. optimal medical therapy in severe secondary MR yielded virtually opposite conclusions. We reviewed current evidence to identify predictors of PMVR-related outcomes in secondary MR useful to improve the timing and the selection of patients who would derive maximal benefit from MitraClip intervention. Beyond mitral valve anatomy, optimal candidate selection should rely on a comprehensive diagnostic workup and a fine-tuned risk stratification process aimed at (i) recognizing the substantial heterogeneity of secondary MR and its complex interaction with the myocardium, (ii) foreseeing hemodynamic consequences of PMVR, (iii) anticipating futility and (iv) improving symptoms, quality of life and overall survival.

Background Transcatheter aortic valve replacement (TAVR) requires large‐bore access, which is associated with bleeding and vascular complications. ProGlide and Prostar XL are vascular closure devices widely used in clinical practice, but their comparative efficacy and safety in TAVR is a subject of debate, owing to conflicting results among published studies. We aimed to compare outcomes with Proglide versus Prostar XL vascular closure devices after TAVR. Methods and Results This large‐scale analysis was conducted using RISPEVA, a multicenter national prospective database of patients undergoing transfemoral TAVR treated with ProGlide versus Prostar XL vascular closure devices. Both multivariate and propensity score adjustments were performed. A total of 2583 patients were selected. Among them, 1361 received ProGlide and 1222 Prostar XL. The predefined primary end point was a composite of cardiovascular mortality, bleeding, and vascular complications assessed at 30 days and 1‐year follow‐up. At 30 days, there was a significantly greater reduction of the primary end point with ProGlide versus Prostar XL (13.8% versus 20.5%, respectively; multivariate adjusted odds ratio, 0.80 [95% CI, 0.65–0.99]; P=0.043), driven by a reduction of bleeding complications (9.1% versus 11.7%, respectively; multivariate adjusted odds ratio, 0.76 [95% CI, 0.58–0.98]; P=0.046). Propensity score analysis confirmed the significant reduction of major adverse cardiovascular events and bleeding risk with ProGlide. No significant differences in the primary end point were found between the 2 vascular closure devices at 1 year of follow‐up (multivariate adjusted hazard ratio, 0.88 [95% CI, 0.72–1.10]; P=0.902). Comparable results were obtained by propensity score analysis. During the procedure, compared with Prostar XL, ProGlide yielded significant higher device success (99.2% versus 97.5%, respectively; P=0.001). Conclusions ProGlide has superior efficacy as compared with Prostar XL in TAVR procedures and is associated with a greater reduction of composite adverse events at short‐term, driven by lower bleeding complications. Registration Information URL: clini​caltr​ials.gov; Unique identifier: NCT02713932.

Background: Transcatheter aortic valve replacement (TAVR) has been validated for the treatment of severe symptomatic aortic stenosis in patients at high and intermediate surgical risk. Recently, TAVR has been proposed as an alternative to medical therapy in inoperable patients with severe native aortic valve regurgitation (NAVR). This multicenter international registry sought to evaluate safety and efficacy of TAVR with the self-expandable ACURATE neo valve in a cohort of patients with NAVR. Methods: A total of 24 patients with severe NAVR treated by TAVR between September 2016 and October 2018 in 13 European centers were included. Clinical, procedural and follow up data were inserted in a dedicated database. Outcomes were codified according to Valve Academic Research Consortium-2 criteria. Results: Mean age was 79.4 years, 58.4% were female. Mean EuroSCORE II and STS score were 5% and 3.9%, respectively. Device success was 87.5%. Moderate paravalvular leak (PVL) was found in two (8.3%) of patients, both with a perimeter oversizing index

Background: Thin strut 3rd generation drug eluting stents offer the potential advantage over the previous generation of better technical performance and reduced neointimal proliferation parameters, which are linked to mid and late term device failure. Aim: To evaluate the performance of the Xlimus sirolimus-eluting stent (SES) against the Synergy everolimus-eluting stent (EES) in terms of device reendothelialization in patients undergoing PCI for coronary artery disease (CAD). Methods: XLIMIT is a multicenter randomized controlled trial targeting 180 patients requiring percutaneous coronary interventions (PCI). Patients will be treated with Xlimus SES or Synergy EES implantation and randomization will be performed in a 2:1 ratio. The primary endpoint will be the reendothelialization grade of the Xlimus stent in terms of strut coverage and neointimal hyperplasia volume as compared to Synergy. Secondary endpoints will be represented by clinical and procedural outcomes. The first patient was enrolled on February 2019. Conclusions: A clearer understanding of the endothelialization process of new generation DES could significantly impact the treatment with dual antiplatelet therapy in the future. Moreover, although not powered for clinical end-points, the XLIMIT trial will provide randomized data in a population with minimal exclusion criteria. Trial registration: ClinicalTrials.gov Identifier: NCT03745053. Registered on November 19, 2018. Keywords: Clinical trials, Drug-eluting stent, Coronary artery disease

Intermediate progenitors (IPs) amplify the production of pyramidal neurons, but their role in selective genesis of cortical layers or neuronal subtypes remains unclear. Using genetic lineage tracing in mice, we find that IPs destined to produce upper cortical layers first appear early in corticogenesis, by embryonic day 11.5. During later corticogenesis, IP laminar fates are progressively limited to upper layers. We examined the role of Tbr2, an IP-specific transcription factor, in laminar fate regulation using Tbr2 conditional mutant mice. Upon Tbr2 inactivation, fewer neurons were produced by immediate differentiation and laminar fates were shifted upward. Genesis of subventricular mitoses was, however, not reduced in the context of a Tbr2-null cortex. Instead, neuronal and laminar differentiation were disrupted and delayed. Our findings indicate that upper-layer genesis depends on IPs from many stages of corticogenesis and that Tbr2 regulates the tempo of laminar fate implementation for all cortical layers.

Background: Surgically implanted aortic bio-prostheses are prone to degeneration and eventually failure within 10 to 20 years. Transcatheter aortic valve replacement “valve-in-valve” (TAVR-VIV) is an effective treatment for patients deemed at prohibitive risk for surgical redo. However, Mitroflow, Freedom, Toronto and Freestyle bioprostheses pose a high risk of left main obstruction and are only marginally represented in the available literature. Methods and Results After evaluation of local Heart Team, TAVR-VIV implantation was performed in 20 patients with a failed Mitroflow (8), Freedom (5), Toronto SPV (3), Freestyle (2), Trifecta (1), or Mosaic (1) bioprostheses. Patients/prostheses were divided in type A (mainly stenotic, 8 pts), and type B (mainly regurgitant, 12 pts). All patients were managed protecting the left main ostium. At 30 days, 2 fatalities (10%) and 2 myocardial infarction (10%) occurred. At a mean follow up of 6 months, 2 further fatalities (cumulative survival rate of 80%) were observed (cumulative incidence of 5%). Conclusions This registry specifically focusing on extremely high risk TAVR-VIV is a proof of concept. The protection of the left main during the procedure allows patients initially deemed at highest or even prohibitive risk to be successfully treated and further support the use of bioprostheses at the time of the surgical treatment.

Epigenetic factors (EFs) regulate multiple aspects of cerebral cortex development, including proliferation, differentiation, laminar fate, and regional identity. The same neurodevelopmental processes are also regulated by transcription factors (TFs), notably the Pax6→ Tbr2→ Tbr1 cascade expressed sequentially in radial glial progenitors (RGPs), intermediate progenitors, and postmitotic projection neurons, respectively. Here, we studied the EF landscape and its regulation in embryonic mouse neocortex. Microarray and in situ hybridization assays revealed that many EF genes are expressed in specific cortical cell types, such as intermediate progenitors, or in rostrocaudal gradients. Furthermore, many EF genes are directly bound and transcriptionally regulated by Pax6, Tbr2, or Tbr1, as determined by chromatin immunoprecipitation-sequencing and gene expression analysis of TF mutant cortices. Our analysis demonstrated that Pax6, Tbr2, and Tbr1 form a direct feedforward genetic cascade, with direct feedback repression. Results also revealed that each TF regulates multiple EF genes that control DNA methylation, histone marks, chromatin remodeling, and non-coding RNA. For example, Tbr1 activates Rybp and Auts2 to promote the formation of non-canonical Polycomb repressive complex 1 (PRC1). Also, Pax6, Tbr2, and Tbr1 collectively drive massive changes in the subunit isoform composition of BAF chromatin remodeling complexes during differentiation: for example, a novel switch from Bcl7c (Baf40c) to Bcl7a (Baf40a), the latter directly activated by Tbr2. Of 11 subunits predominantly in neuronal BAF, 7 were transcriptionally activated by Pax6, Tbr2, or Tbr1. Using EFs, Pax6→ Tbr2→ Tbr1 effect persistent changes of gene expression in cell lineages, to propagate features such as regional and laminar identity from progenitors to neurons.

BackgroundThe use of embolic protection devices (EPD) may theoretically reduce the occurrence of cerebral embolic lesions during transcatheter aortic valve implantation. Available evidence from single studies is inconclusive. The aim of the present meta‐analysis was to assess the safety and efficacy profile of current EPD. Methods and ResultsMajor medical databases were searched up to December 2017 for studies that evaluated patients undergoing transcatheter aortic valve implantation with or without EPD. End points of interest were 30‐day mortality, 30‐day stroke, the total number of new lesions, the ischemic volume per lesion, and the total volume of lesions. Eight studies involving 1285 patients were included. The EPD delivery success rate was reported in all studies and was achieved in 94.5% of patients. The use of EPD was not associated with significant differences in terms of 30‐day mortality (odds ratio 0.43 [0.18–1.05], P=0.3) but it was associated with a lower rate of 30‐day stroke (odds ratio 0.55 [0.31–0.98], P=0.04). No differences were detected with respect to the number of new lesions (standardized mean difference −0.19 [−0.71 to 0.34], P=0.49). The use of EPD was associated with a significantly smaller ischemic volume per lesion (standardized mean difference, −0.52 [−0.85 to −0.20], P=0.002) and smaller total volume of lesions (standardized mean difference, −0.23 [−0.42 to −0.03], P=0.02). ConclusionsThe use of EPD is not associated with a reduced rate of mortality and new ischemic cerebral lesions. The use of EPD during transcatheter aortic valve implantation seems to be associated with a lower 30‐day stroke rate, although this result is driven by a single nonrandomized study. The use of EPD is associated with a smaller volume of ischemic lesions, and smaller total volume of ischemic lesions.

The optimal treatment of unprotected left main (UPLM) with either PCI or CABG remains uncertain.The purpose of this study was to determine the comparative safety and efficacy of PCI versus CABG in patients with UPLM disease.Search of BioMedCentral, CENTRAL, mRCT, PubMed, major cardiological congresses proceedings and references cross-check (updated November 2016). Outcomes were the rate of MACE [all cause death, MI, stroke], the rates of the individual components of MACE and the rate of target vessel revascularisation (TVR).We identified 6 Randomised Controlled Trials totalling 4717 patients allocated to PCI or CABG. At 1 year follow up, PCI and CABG were substantially equivalent with respect to the rates of MACE [PCI 8.5% vs CABG 8.9%, OR 1.02,(0.76-1.36), p = 0.9], death [PCI 5.4% vs CABG 6.6%, OR 0.81,(0.63-1.03),p = 0.08] and MI [PCI 3.4% vs CABG 4.3%, OR 0.80(0.59-1.07), p = 0.14]. Notably, PCI was associated with a significantly lower rate of stroke [PCI 0.6% vs CABG 1.8%, OR 0.36,(0.17-0.79), p = 0.01] and with a significantly higher rate of TVR [PCI 8.7% vs CABG 4.5%, OR 2.00(1.46-2.75), p

MECP2 mutations cause a number of neurological disorders of which Rett syndrome (RTT) represents the most thoroughly analysed condition. Many Mecp2 mouse models have been generated through the years; their validity is demonstrated by the presence of a broad spectrum of phenotypes largely mimicking those manifested by RTT patients. These mouse models, between which the C57BL/6 Mecp2tm1.1Bird strain probably represents the most used, enabled to disclose much of the roles of Mecp2. However, small litters with little viability and poor maternal care hamper the maintenance of the colony, thus limiting research on such animals. For this reason, past studies often used Mecp2 mouse models on mixed genetic backgrounds, thus opening questions on whether modifier genes could be responsible for at least part of the described effects. To verify this possibility, and facilitate the maintenance of the Mecp2 colony, we transferred the Mecp2tm1.1Bird allele on the stronger CD1 background. The CD1 strain is easier to maintain and largely recapitulates the phenotypes already described in Mecp2-null mice. We believe that this mouse model will foster the research on RTT.

In the last years, the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with epileptic encephalopathies characterized by the early onset of intractable epilepsy, severe developmental delay, autistic features, and often the development of Rett syndrome-like features. Still, the role of CDKL5 in neuronal functions is not fully understood. By way of a yeast two hybrid screening we identified the interaction of CDKL5 with shootin1, a brain specific protein acting as a determinant of axon formation during neuronal polarization. We found evidence that CDKL5 is involved, at least in part, in regulating neuronal polarization through its interaction with shootin1. Indeed, the two proteins interact in vivo and both are localized in the distal tip of outgrowing axons. By using primary hippocampal neurons as model system we find that adequate CDKL5 levels are required for axon specification. In fact, a significant number of neurons overexpressing CDKL5 is characterized by supernumerary axons, while the silencing of CDKL5 disrupts neuronal polarization. Interestingly, shootin1 phosphorylation is reduced in neurons silenced for CDKL5 suggesting that the kinase affects, directly or indirectly, the post-translational modification of shootin1. Finally, we find that the capacity of CDKL5 to generate surplus axons is attenuated in neurons with reduced shootin1 levels, in agreement with the notion that two proteins act in a common pathway. Altogether, these results point to a role of CDKL5 in the early steps of neuronal differentiation that can be explained, at least in part, by its association with shootin1.

Exposure to stress during pregnancy influences the trajectory of brain development resulting in permanent alterations that may contribute to increased susceptibility to subsequent cognitive or neuropsychiatric disorders. In this manuscript, we examined the effects of prenatal stress on the expression of basic fibroblast growth factor (FGF-2), an important molecular regulator of development and plasticity, in adult male rats under basal conditions as well as in response to acute or chronic stress. Baseline FGF-2 mRNA levels were differentially influenced by gestational stress in a variety of brain regions, with significant decreases in prefrontal cortex and increases in entorhinal cortex and striatum. By itself, postnatal stress similarly decreased trophic factor expression in prefrontal cortex while evoking stimulation elsewhere. Gestational stress altered the pattern of FGF-2 expression in response to adult stress, completely reversing the pattern in the prefrontal cortex (stimulatory instead of inhibitory), blunting the response in the entorhinal cortex and desensitizing the response in the striatum. These effects point to a unique interference of chronic prenatal stress with both ongoing FGF-2 expression and its responses to subsequent stressors, lasting into adulthood.Given the multifaceted role of FGF-2 in synaptic development, maintenance and plasticity, these data provide detailed mechanistic evidence as to how prenatal stress elicits lifelong effects on synaptic function. The abnormal modulation of FGF-2 gene expression in specific brain regions in response to subsequent stress in adulthood may impair the normal adaptive responses of the cell to challenging situations.

In the last few years, the X-linked serine/threonine kinase cyclin-dependent kinase-like 5 (CDKL5) has been associated with early-onset epileptic encephalopathies characterized by the manifestation of intractable epilepsy within the first weeks of life, severe developmental delay, profound hypotonia, and often the presence of some Rett-syndrome-like features. The association of CDKL5 with neurodevelopmental disorders and its high expression levels in the maturing brain underscore the importance of this kinase for proper brain development. However, our present knowledge of CDKL5 functions is still rather limited. The picture that emerges from the molecular and cellular studies suggests that CDKL5 functions are important for regulating both neuronal morphology through cytoplasmic signaling pathways and activity-dependent gene expression in the nuclear compartment. This paper surveys the current state of CDKL5 research with emphasis on the clinical symptoms associated with mutations in CDKL5, the different mechanisms regulating its functions, and the connected molecular pathways. Finally, based on the available data we speculate that CDKL5 might play a role in neuronal plasticity and we adduce and discuss some possible arguments supporting this hypothesis.