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Left atrial appendage closure (LAAC) is a crucial intervention for stroke prevention in patients with non-valvular atrial fibrillation who are unsuitable for long-term anticoagulation. Amulet and Watchman are the most implanted devices worldwide for performing LAAC, and the aim of this review is to provide a comprehensive comparison focusing on their efficacy, safety, and short- and long-term outcomes. The Watchman device, the first to gain FDA approval, has been extensively studied and demonstrates significant reductions in stroke and systemic embolism rates. The Amulet device, a newer alternative, promises enhanced design features for more efficient appendage sealing. Current data highlight that both devices offer similar efficacy and safety for LAAC. While the two devices differ in terms of intraprocedural complication rates, they offer similar short- to long-term outcomes in terms of peri-device leaks, device-related thrombosis, and mortality. Both devices are indicated for patients who are unable to tolerate OAC, given their similar risk and safety profiles. Newer clinical studies are directed at establishing the efficacy of both devices as the primary method for stroke prevention in AF as an alternative to OAC.

Introduction: Recent 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., Methods: This 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., Results: The 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., Conclusion: In 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., Competing Interests: SB has been a consultant for Abbot and Boston Scientific Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Bonanni, Frazzetto, Nardone, Meucci, Musto, Quaranta, Saccà, Bedogni, Maffeo, Ugo, Guarracini, Bocuzzi, Durante, Granatelli, Tumminello, Eusebio, Grasso, De Marco, Cortese, Mariani and Berti.)

Competing Interests: Dr Barbanti is consultant for Medtronic, Edwards Lifescience and Boston Scientific. Dr Tamburino is consultant for Medtronic. Dr Grasso is proctor for Abbott, Boston Scientific and Eclipse Medical. Dr Di Salvo is proctor for Gore, Lifetech, Occlutech, and Innova Medical.

Background: Concomitant mitral transcatheter edge-to-edge repair (M-TEER) and left atrial appendage closure (LAAC) showed to be a feasible approach to optimize the treatment of patients eligible for both procedures, but mid-term outcomes are unclear., Methods: We retrospectively analyzed consecutive patients undergoing M-TEER and enrolled in the local prospective Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation (GRASP) registry. We compared patients undergoing isolated M-TEER ( n = 58, 58.5%) with those undergoing concomitant M-TEER and LAAC ( n = 41, 41.5%) from January 2018 to December 2022. The primary endpoint was a composite of all-cause death, stroke or systemic embolism, hospitalization for heart failure, and bleeding at 1 year. The co-primary endpoint was procedural success., Results: The primary endpoint was similar between patients undergoing concomitant M-TEER+LAAC or isolated M-TEER (Kaplan Meier (KM) estimates 36.6% vs. 44.8%; p log-rank = 0.75). Procedural success was also similar (92.7% vs. 94.8%; p = 0.69). At 1- year, minor bleeds were lower in patients undergoing concomitant M-TEER and LAAC (KM estimates 0.0% vs. 18.9%; p log-rank < 0.01)., Conclusion: In patients with concomitant MR and AF and eligible for M-TEER and LAAC treatment, a combined approach of M-TEER and LAAC was as safe as an M-TEER-alone strategy and associated with lower minor bleeding at 1 year.

While mitral stenosis of rheumatic origin has been effectively treated percutaneously for more than 20 years, transcatheter treatment of mitral (MR) and tricuspid (TR) regurgitation appears as a contemporary unmet clinical need. The advent of new transcatheter therapies offers several treatment options for elderly and frail patients at high surgical risk. MitraClip is now consolidated as a therapy for functional MR in selected patients. Transcatheter mitral valve replacement is a promising alternative to transcatheter repair, for both functional and degenerative forms. However, further developments and new evidence are needed. Transcatheter treatment of the tricuspid valve has arrived late compared to similar technologies that have been developed for the aortic and mitral valve, and is currently in its infancy. This is likely due, in part, to the previously underreported impact of TR on patient outcomes. Edge-to-edge repair is the most advanced transcatheter solution in development. Data on annuloplasty and tricuspid valve replacement are limited and more evidence is needed. The future looks promising for transcatheter mitral and tricuspid valve therapies, although their place in clinical practice has yet to be clearly defined., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: The Watchman-FLX left atrial appendage closure (LAAC) device presents innovative features: higher conformability, reduced length, closed distal "flex-ball" during deployment, and flattened surface. We report our real-world experience with the Watchman-FLX device in two centers with consolidated LAAC expertise., Methods: We enrolled 200 consecutive Watchman-FLX patients (2019-2021) in a nonrandomized double-center registry; procedural data and follow-up for midterm clinical outcomes were collected. A control group of 100 patients treated with first-generation Watchman (2.5) was included., Results: According to mean CHAD 2 DS 2 -VASc (5 ± 1.40) and HAS-BLED (3.8 ± 1.01) scores, the population included in this study was at high risk: 29% had a previous stroke and 56.5% a bleeding event. Main LAAC indications were symptomatic hemorrhage (39.5%), need for triple antithrombotic therapy (39%), gastrointestinal bleeding (32%), and oral anticoagulation intolerance (18%). Transesophageal echocardiography guidance was followed in 93% of cases (48% in general anesthesia and 45% under conscious sedation). Repositioning an FLX device was required in 20% of cases and no complication occurred. In 96% of patients, the first selected device was delivered, while in 4% a device size change was required after the first choice (7% with Watchman 2.5). Peridevice leaks (<5 mm) were found postimplant in two cases (1%). Overall, the procedural success rate was 99.5%. One patient's procedure was unsuccessful (0.5%), due to left atrial appendage (LAA) anatomy; differently, the mean failure rate with Watchman 2.5 was 2%. No device embolization was reported. Complications (8.5%) were mainly related to the access site (3%); major bleedings (1%), and in-hospital death (0.5%) rarely occurred. After a follow-up of 272 ± 173 days, 2.3% of cases experienced a non-device-related stroke and 0.6% fatal bleeding., Conclusion: Our registry showed a high procedural success rate of the Watchman-FLX in a high-risk population. According to our experience, the main advantages include easy implanting and repositioning, absence of embolization, good LAA sealing, and low rate of complications in the follow-up period., (© 2022 Wiley Periodicals LLC.)

Background: The effect of direct oral anticoagulants (DOACs) on evolution of a post-thrombotic syndrome (PTS) is unknown., Methods and Results: This retrospective study included patients (n = 98) with a PTS occurring after a proximal deep-vein thrombosis (DVT). The PTS progression was assessed by the Villalta scale change over time from when patients were started on DOACs for the prevention of DVT recurrence according to current guidelines. The PTS evolution was compared between patients with good (n = 63) vs. poor (n = 35) DOACs adherence, defined by using a medication possession ratio cut point of 0.80. The mean follow-up was 41.7 ± 17.7 and 27.5 ± 10.5 months in patients with good or poor adherence, respectively. The primary endpoint of PTS improvement (defined when the Villalta score became <5 and/or decreased by ≥30% from baseline) was higher in patients with good vs. poor adherence (66.7% vs. 20%, p < 0.001). None of the patients in the good adherence group experienced at any time of follow-up the co-primary endpoint of PTS worsening (defined as the Villalta score increase ≥30%), which instead occurred in 12 (34.3%) of those with poor adherence (p < 0.001). All study-defined primary endpoints occurred within 2 years. The mean values of the Villalta partial scores related to the subjective symptoms (patient-rated) and to the potentially reversible physician-rated signs were significantly improved in the good adherence group, while they were unchanged among patients with poor adherence., Conclusions: In this study a good vs. poor DOACs adherence was associated with a more favorable progression of PTS over a long-term follow-up. Larger studies are needed to explore the clinical efficacy of DOACs on PTS manifestations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Current medication adherence telemonitoring systems have several limitations prompting the need for simpler, low-cost and widely applicable tools. To meet these needs, we propose a novel method consisting in sending a digital feedback of medication intake by just reading a pre-defined Quick Response (QR) code attached on the pills box., Methods: To assess the potential clinical applicability of the proposed QR code-based task, its feasibility was tested among elderly with heart diseases. The primary endpoint was the learning success defined as a correct execution of all QR code-based digital task steps within 10 min. Study outcomes were compared between patients 65-75 years old (younger cohort) and those aged >75 years (older cohort) admitted to the Cardiology ward of a tertiary center., Results: A total of 262 patients were included: 128 (48.9%) were younger and 134 (51.1%) older. Despite a baseline low smartphone use in the overall population (41.2%), patients learning success of the digital task was as high as 75.6%, with lower rates among older vs. younger (67.9% vs. 83.6%, p = 0.005). After adjustment no significant independent association between age and success in learning the QR code-based task was found. Differently, increasing age was a negative independent predictor of smartphone use. The learning time was overall small, but longer in the older group (126 ± 100 vs. 100 ± 60 s, p = 0.03)., Conclusions: The QR code-based digital task was highly feasible for elderly with heart diseases suggesting its potential large-scale clinical application and encouraging the investigation of QR code-based systems for medication adherence telemonitoring., Competing Interests: Declaration of Competing Interest All Authors have no conflict of interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Subjects with Neurofibromatosis 1 (NF1) develop vascular complications. The protein product of the gene affected in NF1, neurofibromin, physiologically modulates endothelial function and preserves vascular and myocardial structure. Our study aimed to verify whether subjects with NF1 have early, preclinical abnormalities of carotid artery structure, brachial artery function, and cardiac function. We recruited 22 NF1 subjects without previous cardiovascular events and 22 healthy control subjects. All subjects underwent measurement of carotid artery intima-media thickness (IMT), evaluation of brachial artery endothelial function after ischemia and exercise, and cardiac function. Mean IMT was 543 ± 115 μ in NF1 subjects and 487 ± 70 μ in Controls (p < 0.01). Endothelial function was significantly dumped in NF1 subjects. The dilation after ischemia and exercise was respectively 7.5(± 4.8)% and 6.7(± 3.0)% in NF1 versus 10.5(± 1.2)% and 10.5(± 2.1)% in control subjects (p < 0.02; p < 0.002). Left ventricular systolic function assessed by Global Longitudinal Strain was significantly different between NF1 subjects and Controls: - 19.3(± 1.7)% versus - 21.5(± 2.7)% (p < 0.008). These findings demonstrate that NF1 patients have early morphological and functional abnormalities of peripheral arteries and systolic cardiac impairment and suggest the need for a tight cardiovascular risk evaluation and primary prevention in subjects with NF1.

Empagliflozin reduces the risk of cardiovascular mortality in subjects with type 2 diabetes. We demonstrated that empagliflozin increases blood viscosity and carotid shear stress and decreases carotid wall thickness. Shear stress is the force acting on the endothelial surface and modulates arterial function. The current study evaluates the influence of empagliflozin on brachial artery shear stress and endothelial function compared to incretin-based therapy. The study is a nonrandomized, open, prospective cohort study including 35 subjects with type 2 diabetes administered empagliflozin or incretin-based therapy. Shear stress was calculated with a validated formula, and endothelial function was evaluated using the flow-mediated dilation technique. Both treatments resulted in comparable reductions in blood glucose and glycated haemoglobin. Brachial artery shear stress significantly increased exclusively in the empagliflozin group (61 ± 20 vs 68 ± 25 dynes/cm 2 , p  = 0.04), whereas no significant difference was detected in the incretin-based therapy group (60 ± 20 vs 55 ± 12 dynes/cm 2 , p  = not significant). Flow-mediated dilation significantly increased in the empagliflozin group (4.8 ± 4.5% vs 8.5 ± 5.6%, p  = 0.03). Again, no change was detected in the incretin-based therapy group (5.1 ± 4.5% vs 4.7 ± 4.7%, p  = not significant). The present findings demonstrate the beneficial effect of empagliflozin on shear stress and endothelial function in subjects with type 2 diabetes independent of the hypoglycaemic effect.

The thiazolidinedione, compound 1 , has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound 1 could introduce isoform selectivity. We report the synthesis, characterization, and inhibitory activity of a novel series of 4-iminothiazolidin-2-ones for inhibition of the class I PI3K isoforms. Their synthesis was successfully achieved by multiple pathways described in this paper. Initial in vitro data of 28 analogues demonstrated poor inhibition of all class I PI3K isoforms. However, we identified an alternate target, the phosphodiesterases, and present preliminary screening results showing improved inhibitory activity.

CYT997 is a wholly synthetic compound that possesses highly potent cytotoxic activity in vitro through inhibition of microtubule polymerization. CYT997 blocks the cell cycle at the G(2)-M boundary, and Western blot analysis indicates an increase in phosphorylated Bcl-2, along with increased expression of cyclin B1. Caspase-3 activation is also observed in cells treated with CYT997 along with the generation of poly(ADP-ribose) polymerase. The compound possesses favorable pharmacokinetic properties, is orally bioavailable, and is efficacious per os in a range of in vivo cancer models, including some refractory to paclitaxel treatment. CYT997 exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 possesses a useful combination of pharmacologic and pharmacokinetic properties and has considerable potential as a novel anticancer agent.

The last few years have seen the identification of numerous small molecules that selectively inhibit specific class I isoforms of PI3K (phosphoinositide 3-kinase), yet little has been revealed about the molecular basis for the observed selectivities. Using site-directed mutagenesis, we have investigated one of the areas postulated as being critical to the observed selectivity. The residues Thr(886) and Lys(890) of the PI3Kgamma isoform project towards the ATP-binding pocket at the entrance to the catalytic site, but are not conserved. We have made reciprocal mutations between those residues in the beta isoform (Glu(858) and Asp(862)) and those in the alpha isoform (His(855) and Gln(859)) and evaluated the potency of a range of reported PI3K inhibitors. The results show that the potencies of beta-selective inhibitors TGX221 and TGX286 are unaffected by this change. In contrast, close analogues of these compounds, particularly the alpha-isoform-selective compound (III), are markedly influenced by the point mutations. The collected data suggests two distinct binding poses for these inhibitor classes, one of which is associated with potent PI3Kbeta activity and is not associated with the mutated residues, and a second that, in accord with earlier hypotheses, does involve this pair of non-conserved amino acids at the catalytic site entrance and contributes to the alpha-isoform-selectivity of the compounds studied.

Binding of the platelet GPIb/V/IX (glycoprotein Ib/V/IX) receptor to von Willebrand factor is critical for platelet adhesion and aggregation under conditions of rapid blood flow. The adhesive function of GPIbalpha is regulated by its anchorage to the membrane skeleton through a specific interaction with filamin A. In the present study, we examined the amino acid residues within the cytoplasmic tail of GPIbalpha, which are critical for association with filamin A, using a series of 25-mer synthetic peptides that mimic the cytoplasmic tail sequences of wild-type and mutant forms of GPIbalpha. Peptide binding studies of purified human filamin A have demonstrated a major role for the conserved hydrophobic stretch L567FLWV571 in mediating this interaction. Progressive alanine substitutions of triple, double and single amino acid residues within the Pro561-Arg572 region suggested an important role for Trp570 and Phe568 in promoting GPIbalpha binding to filamin A. The importance of these two residues in promoting filamin A binding to GPIbalpha in vivo was confirmed from the study of Chinese-hamster ovary cells expressing GPIbalpha Trp570-->Ala and Phe568-->Ala substitutions. Phenotypic analysis of these cell lines in flow-based adhesion studies revealed a critical role for these residues in maintaining receptor anchorage to the membrane skeleton and in maintaining cell adhesion to a von Willebrand factor matrix under high-shear conditions. These studies demonstrate a novel filamin A binding motif in the cytoplasmic tail of GPIbalpha, which is critically dependent on both Trp570 and Phe568.