Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation.

BACKGROUND: Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. METHODS: Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies. RESULTS: Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutrophil adhesion to End.PTP1B-KO endothelial cells in vitro. Circulating levels of annexin V+ procoagulant endothelial CD62E+ (E-selectin) and neutrophil (Ly6G+) extracellular vesicles were also elevated in End.PTP1B-KO mice after inferior vena cava ligation. Higher plasma MPO (myeloperoxidase) and Cit-H3 (citrullinated histone-3) levels and neutrophil elastase activity indicated neutrophil activation and extracellular trap formation. Infusion of End.PTP1B-KO extracellular vesicles into C57BL/6J wild-type mice most prominently enhanced the recruitment of endogenous neutrophils, and this response was blunted in VWF-deficient mice or by VWF-blocking antibodies. Reduced PTP1B binding and tyrosine dephosphorylation of SNAP23 (synaptosome-associated protein 23) resulting in increased VWF exocytosis and neutrophil adhesion were identified as mechanisms, all of which could be restored by NF-κB kinase inhibition using BAY11-7082. CONCLUSIONS: Our findings show that endothelial PTP1B deletion promotes venous thromboinflammation by enhancing SNAP23 phosphorylation, endothelial VWF exocytosis, and neutrophil recruitment.

Fitusiran reduces bleeding in Factor X-deficient mice.

Factor X (FX)-deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aimed to explore the use of fitusiran (an investigational siRNA that silences antithrombin expression) to increase thrombin generation and the in vivo hemostatic potential under conditions of FX-deficiency. We therefore developed a novel model of inducible FX-deficiency, generating mice expressing <1% FX activity and antigen (f10low-mice). Compared to control f10WT-mice, f10low-mice had 6- and 4-fold prolonged clotting times in Prothrombin Time- and activated Partial Prothrombin Time-assays, respectively (p<0.001). Thrombin generation was severely reduced, irrespective whether tissue factor or factor XIa was used as initiator. In vivo analysis revealed near-absent thrombus formation in a laser-induced vessel injury-model. Furthermore, in two distinct bleeding models, f10low-mice displayed an increased bleeding tendency compared to f10WT-mice. In the tail-clip assay blood loss was increased from 12±16 microliter to 590±335 microliter (p<0.0001). In the saphenous vein puncture (SVP)-model, the number of clots generated was reduced from 19±5 clots/30 min for f10WT-mice to 2±2 clots/30 min (p<0.0001) for f10low-mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low-mice with fitusiran (2x10 mg/kg at one-week interval) resulted in 17±6% residual antithrombin activity and increased thrombin generation (4-fold and 2-3-fold increase in endogenous thrombin potential and thrombin peak, respectively). In the SVP-model, the number of clots was increased to 8±6 clots/30 min (p=0.0029). Altogether, we demonstrate that reduction of antithrombin levels is associated with improved hemostatic activity under conditions of FX-deficiency.

Optimization of Absolute Coronary Blood Flow Measurements to Assess Microvascular Function: In Vivo Validation of Hyperemia and Higher Infusion Speeds.

BACKGROUND: Reliable assessment of coronary microvascular function is essential. Techniques to measure absolute coronary blood flow are promising but need validation. The objectives of this study were: first, to validate the potential of saline infusion to generate maximum hyperemia in vivo. Second, to validate absolute coronary blood flow measured with continuous coronary thermodilution at high (40-50 mL/min) infusion speeds and asses its safety. METHODS: Fourteen closed-chest sheep underwent absolute coronary blood flow measurements with increasing saline infusion speeds at different dosages under general anesthesia. An additional 7 open-chest sheep underwent these measurements with epicardial Doppler flow probes. Coronary flows were compared with reactive hyperemia after 45 s of coronary occlusion. RESULTS: Twenty milliliters per minute of saline infusion induced a significantly lower hyperemic coronary flow (140 versus 191 mL/min; P=0.0165), lower coronary flow reserve (1.82 versus 3.21; P≤0.0001), and higher coronary resistance (655 versus 422 woods units; P=0.0053) than coronary occlusion. On the other hand, 30 mL/min of saline infusion resulted in hyperemic coronary flow (196 versus 192 mL/min; P=0.8292), coronary flow reserve (2.77 versus 3.21; P=0.1107), and coronary resistance (415 versus 422 woods units; P=0.9181) that were not different from coronary occlusion. Hyperemic coronary flow was 40.7% with 5 mL/min, 40.8% with 10 mL/min, 73.1% with 20 mL/min, 102.3% with 30 mL/min, 99.0% with 40 mL/min, and 98.0% with 50 mL/min of saline infusion when compared with postocclusive hyperemic flow. There was a significant bias toward flow overestimation (Bland-Altman: bias±SD, -73.09±30.52; 95% limits of agreement, -132.9 to -13.27) with 40 to 50 mL/min of saline. Occasionally, ischemic changes resulted in ventricular fibrillation (9.5% with 50 mL/min) at higher infusion rates. CONCLUSIONS: Continuous saline infusion of 30 mL/min but not 20 mL/min induced maximal hyperemia. Absolute coronary blood flow measured with saline infusion speeds of 40 to 50 mL/min was not accurate and not safe.

Transcatheter valve-in-valve implantation treatment with the J-valve system for tricuspid bioprosthesis deterioration: a report of two cases.

Background: Patients with tricuspid bioprosthetic structural valve degeneration (SVD) often present with right ventricular enlargement and severe dysfunction, which cause a higher risk for redo cardiac surgery. In 2019, our center innovated using the J-valve system for valve-in-valve (ViV) implantation to treat tricuspid bioprosthetic SVD. The purpose of this study was to summarize the clinical effect after 1-year follow-up. Case Description: From April 2019 to October 2019, two cases of tricuspid bioprosthetic dysfunction were treated with the J-valve system. Both patients were male, aged 46 and 67 years, respectively. The preoperative evaluation showed that the risk of conventional redo open heart surgery was high. The J-valve implantation was successful in both cases. One patient had slight valve displacement when the transporter was withdrawn during the operation, and a second J-valve was implanted in an ideal position. There was no death, no delayed valve displacement, and no readmission during the follow-up period of 12 months. In both cases, there was an absence of trace tricuspid regurgitation. After 6 months of anticoagulation with warfarin, the patients were converted to long-term aspirin treatment. Conclusions: The ViV technique with J-valve is feasible and effective in treating tricuspid bioprosthetic SVD in high-risk patients, avoiding cardiopulmonary bypass and conventional thoracotomy injury.

Transcatheter aortic valve implantation versus surgical aortic valve replacement in severe aortic stenosis patients at low surgical mortality risk: a cost-effectiveness analysis in Belgium.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 device has recently shown significant clinical benefits, compared to surgical aortic valve replacement (SAVR), in patients at low risk for surgical mortality (PARTNER 3 trial, NCT02675114). Currently in Belgium, TAVI use is restricted to high-risk or inoperable patients with severe symptomatic aortic stenosis (sSAS). This cost-utility analysis aimed to assess whether TAVI with SAPIEN 3 could lead to potential cost-savings compared with SAVR, in the low-risk sSAS population in Belgium. METHODS: A previously published, two-stage, Markov-based cost-utility model was used. Clinical outcomes were captured using data from PARTNER 3 and the model was adapted for the Belgian context using cost data from the perspective of the Belgian National Healthcare System, indexed to 2022. A lifetime horizon was chosen. The model outputs included changes in direct healthcare costs, survival and health-related quality of life using TAVI versus SAVR. RESULTS: TAVI with SAPIEN 3 provides meaningful clinical and cost benefits over SAVR, in terms of an increase in quality-adjusted life years (QALYs) of 0.94 and cost-saving of €3 013 per patient. While initial procedure costs were higher for TAVI compared with SAVR, costs related to rehabilitation, disabling stroke, treated atrial fibrillation, and rehospitalization were lower. The cost-effectiveness of TAVI over SAVR remained robust in sensitivity analyses. CONCLUSION: TAVI with SAPIEN 3 may offer a meaningful alternative intervention to SAVR in Belgian low-risk patients with sSAS, showing both clinical benefits and cost savings associated with post-procedure patient management.

An interventional sheep model of severe aortic valve stenosis hemodynamics for the evaluation of alterations in coronary physiology and microvascular function.

We aimed to develop a large animal model of subcoronary aortic stenosis (AS) to study intracoronary and microcirculatory hemodynamics. A total of three surgical techniques inducing AS were evaluated in 12 sheep. Suturing the leaflets together around a dilator (n = 2) did not result in severe AS. Suturing of a pericardial patch with a variable opening just below the aortic valve (n = 5) created an AS which was poorly tolerated if the aortic valve area (AVA) was too small (0.38-1.02 cm2), but was feasible with an AVA of 1.2 cm2. However, standardization of aortic regurgitation (AR) with this technique is difficult. Therefore, we opted for implantation of an undersized AV-bioprosthesis with narrowing sutures on the leaflets (n = 5). Overall, five sheep survived the immediate postoperative period of which three had severe AS (one patch and two bioprostheses). The surviving sheep with severe AS developed left ventricular hypertrophy and signs of increased filling-pressures. Intracoronary assessment of physiological indices in these AS sheep pointed toward the development of functional microvascular dysfunction, with a significant increase in coronary resting flow and hyperemic coronary resistance, resulting in a significantly higher index of microvascular resistance (IMR) and lower myocardial resistance reserve (MRR). Microscopic analysis showed myocardial hypertrophy and signs of fibrosis without evidence of capillary rarefaction. In a large animal model of AS, microvascular changes are characterized by increased resting coronary flow and hyperemic coronary resistance resulting in increased IMR and decreased MRR. These physiological changes can influence the interpretation of regularly used coronary indices.NEW & NOTEWORTHY In an animal model of aortic valve stenosis (AS), coronary physiological changes are characterized by increased resting coronary flow and hyperemic coronary resistance. These changes can impact coronary indices frequently used to assess concomitant coronary artery disease (CAD). At this point, the best way to assess and treat CAD in AS remains unclear. Our data suggest that fractional flow reserve may underestimate CAD, and nonhyperemic pressure ratios may overestimate CAD severity before aortic valve replacement.

Transapical Mitral Valve Replacement: 1-Year Results of the Real-World Tendyne European Experience Registry.

BACKGROUND: Early studies of the Tendyne transcatheter mitral valve replacement (TMVR) showed promising results in a small selective cohort. OBJECTIVES: The authors present 1-year data from the currently largest commercial, real-world cohort originating from the investigator-initiated TENDER (Tendyne European Experience) registry. METHODS: All patients from the TENDER registry eligible for 1-year follow-up were included. The primary safety endpoint was 1-year cardiovascular mortality. Primary performance endpoint was reduction of mitral regurgitation (MR) up to 1 year. RESULTS: Among 195 eligible patients undergoing TMVR (median age 77 years [Q1-Q3: 71-81 years], 60% men, median Society of Thoracic Surgeons Predicted Risk of Mortality 5.6% [Q1-Q3: 3.6%-8.9%], 81% in NYHA functional class III or IV, 94% with MR 3+/4+), 31% had "real-world" indications for TMVR (severe mitral annular calcification, prior mitral valve treatment, or others) outside of the instructions for use. The technical success rate was 95%. The cardiovascular mortality rate was 7% at 30 day and 17% at 1 year (all-cause mortality rates were 9% and 29%, respectively). Reintervention or surgery following discharge was 4%, while rates of heart failure hospitalization reduced from 68% in the preceding year to 25% during 1-year follow-up. Durable MR reduction to ≤1+ was achieved in 98% of patients, and at 1 year, 83% were in NYHA functional class I or II. There was no difference in survival and major adverse events between on-label use and "real-world" indications up to 1 year. CONCLUSIONS: This large, real-world, observational registry reports high technical success, durable and complete MR elimination, significant clinical benefits, and a 1-year cardiovascular mortality rate of 17% after Tendyne TMVR. Outcomes were comparable between on-label use and "real-world" indications, offering a safe and efficacious treatment option for patients without alternative treatments. (Tendyne European Experience Registry [TENDER]; NCT04898335).

Bleeding and thrombotic risk of different antiplatelet regimens posttranscatheter edge-to-edge mitral valve repair in patients with an indication for oral anticoagulation: Results from an all-comers national registry.

BACKGROUND: Evidence-based recommendations for antithrombotic treatment in patients who have an indication for oral anticoagulation (OAC) after transcatheter edge-to-edge mitral valve repair (TEER) are lacking. AIMS: To compare bleeding and thrombotic risk for different antithrombotic regimens post-TEER with MitraClip in an unselected population with the need for OACs. METHODS: Bleeding and thrombotic complications (stroke and myocardial infarction) up to 3 months after TEER with mitraclip were evaluated in 322 consecutive pts with an indication for OACs. These endpoints were defined by the Mitral Valve Academic Research Consortium criteria and were compared between two antithrombotic regimens: single antithrombotic therapy with OAC (single ATT) and double/triple ATT with a combination of OAC and aspirin and/or clopidogrel (combined ATT). RESULTS: Collectively, 108 (34%) patients received single ATT, 203 (63%) received double ATT and 11 (3%) received triple ATT. Bleeding events occurred in 67 patients (20.9%), with access site related events being the most frequent cause (37%). Bleeding complications were observed more frequently in the combined ATT group than in the single ATT group: 24% versus 14% [p = 0.03, adjusted RR: 0.55 (0.3-0.98)]. Within the combined group, the bleeding risk was 23% in the double ATT and 45% in the triple ATT group. Thrombotic complications occurred in only three patients (0.9%), and all belonged to the combined ATT group. CONCLUSIONS: In patients with an indication for OACs, withholding of antiplatelet therapy post-TEER with Mitraclip was associated with a 45% reduction in bleeding and without a signal of increased thrombotic risk.

Economical aspects of coronary angiography for diagnostic purposes: a Belgian perspective.

Coronary angiography (CA) is an increasing diagnostic procedure in Belgium. The aim of this analysis was to look at the financial aspects of CA in a large tertiary Belgium hospital to establish if current reimbursement is appropriate. For the analysis of costs we considered the use of the catheterisation laboratory, personnel costs and material costs during multiple weekly periods in the spring of 2023. We calculated that one cathlab needs to perform 8.21 CA's to equal incomes with costs. To allow for a small positive income (200€) for the hospital/cardiologist 9 procedures per cathlab day are required. Our hospital performs a 7 (mean) ± 0.75 (standard deviation) of CA's per cathlab day and therefore does not reach this financial break-even point. Our calculations are on the safe side, since coronary physiological interrogation with fractional flow reserve (FFR) was excluded from this analysis. Nevertheless, this is a cost-effective technique for which no extra reimbursement is foreseen in the current Belgium system.

Transcatheter aortic valve implantation versus sutureless aortic valve replacement: a single-centre cost analysis.

AIMS: Sutureless aortic valve replacement (SU-AVR) and transcatheter aortic valve implantation (TAVI) are both viable therapeutic interventions for aortic stenosis in elderly patients. Meta-analyses show similar all-cause mortality for both techniques albeit with a different pattern of adverse effects. This study means to compare costs and, to a lesser extent, clinical outcomes of both techniques. METHODS: A retrospective single-centre analysis was performed for patients receiving SU-AVR or TAVI from 2008 to 2019. Perioperative clinical data were collected from patient files. Costs were assessed by a cost allocation tool. In an attempt to avoid confounding, propensity score matching was carried out. RESULTS: A total of 368 patients underwent either TAVI (n = 100) or SU-AVR (n = 268). After matching, there were 61 patients per treatment group. Length of stay was significantly longer in the SU-AVR group. Excluding device costs, total expenses for SU-AVR (median: €11,630) were significantly higher than TAVI (median: €9240). For both groups, these costs were mostly incurred on intensive care units, followed by nursing units. Non-medical staff was the largest contributor to expenses. Including device costs, SU-AVR (median: €14,683) was shown to be cost-saving compared to TAVI (median: €24,057). CONCLUSIONS: To conclude, we found SU-AVR to be cost-saving compared to TAVI, largely due to higher device costs associated with the latter. Excluding device costs, TAVI was associated with lower expenses and shorter length of stay. Non-medical staff was the largest source of costs, suggesting length of stay to be a major financial determinant.

Development and validation of an occurrence-based healthy dietary diversity (ORCHID) score easy to operationalise in dietary prevention interventions in older adults: a French study.

Healthy diet and dietary diversity have been associated with healthy ageing. Several scores have been developed to assess dietary diversity or healthy diets in epidemiological studies, but they are not adapted to be used in the context of preventive nutrition interventions. This study aimed to develop an occurrence-based healthy dietary diversity (ORCHID) score easy to implement in the field and to validate it using dietary data from older participants in the latest French food consumption survey (INCA3). The ORCHID score was made of several components representing the consumption occurrences of twenty food groups, in line with French dietary guidelines. The score was then validated using dietary data (namely three 24-h recalls and a food propensity questionnaire) from 696 participants aged 60 years and over in the INCA3 survey. Score validity was evaluated by describing the association of the score with its components, as well as with energy intakes, solid energy density (SED) and the probability of adequate nutrient intakes (assessed by the PANDiet). Higher scores were associated with more points in healthy components such as 'fruits' and 'vegetables' (r = 0·51, and r = 0·54, respectively). The score was positively associated with the PANDiet (r = 0·43) and inversely associated with SED (r = -0·37), while no significant association was found with energy intakes. The ORCHID score was validated as a good proxy of the nutritional quality of French older adults' diets. It could therefore be a useful tool for both public health research and nutrition interventions.

A thrombus is formed by a gradient of platelet activation and procoagulant endothelium.

Background: The contribution of platelets in thrombosis within microcirculation has been extensively documented in the literature. We previously showed, in vivo, that platelet activation revealed by intracellular calcium mobilization was a crucial step in the growth of thrombi following laser-induced injury, a model of thromboinflammation. Objective: Our goal was to investigate the extent of platelet activation and the spatial distribution of platelets throughout a growing thrombus. Methods: We employed a multimodal, correlative microscopy approach and computational biology to study the state of platelets on a growing thrombus obtained after a laser injury. Results: We observed a reversible intracellular platelet calcium mobilization that correlates with the time a platelet resides during thrombus growth. Our bioinformatics analysis displayed the following 3 distinct platelet subpopulations resident within a thrombus: (1) resting, (2) partially activated, and (3) "fully" activated platelets. The spatial distribution of the platelet subpopulations in the thrombus creates a double gradient in both the transversal and longitudinal axis, with the maximal percentage of fully activated platelets close to the site of injury. However, these activated platelets did not express negative phospholipids. The injured endothelium was identified to play a vital role in activating the blood coagulation cascade in this model of thrombosis. Conclusion: Following a laser-induced injury, thrombi are formed by a gradient of activated platelets from the injury site to the periphery of the thrombus. These different activation states of platelets throughout the thrombi regulate the biomechanics of the thrombus. The injured endothelium, rather than platelets, was identified to play a key role in the activation of the blood coagulation cascade in this model of thromboinflammation.

1-Year Outcomes Following Transfemoral Transseptal Transcatheter Mitral Valve Replacement: The HighLife TSMVR Feasibility Study.

BACKGROUND: A significant number of patients with severe mitral regurgitation (MR) are not suitable for either surgical or transcatheter edge-to-edge repair because of high surgical risk or inappropriate mitral valve anatomy. OBJECTIVES: The aim of this study was to evaluate the HighLife Trans-Septal Mitral Valve Replacement (TSMVR) system in patients with symptomatic MR and high surgical risk. METHODS: This prospective, multicenter, nonrandomized feasibility study evaluated the safety and performance of the HighLife TSMVR system in patients with moderate to severe or severe symptomatic MR during 1-year follow-up. Echocardiographic data were assessed at an independent core laboratory. RESULTS: A total of 30 patients (mean age 75.6 years, 27% women, median Society of Thoracic Surgeons score 5.5%) with severe MR (90% with secondary MR, median left ventricular ejection fraction 43%) were treated at 13 sites. In 27 of the 30 patients, the HighLife TSMVR system was implanted successfully (technical success rate 90%). Device success at 30 days was 83%. After 1 year, 5 patients (17%) had died. None of the patients who underwent implantation required mitral valve reintervention. All patients who underwent implantation had no or trace (78%) or mild (22%) MR, the mean gradient of the HighLife valve was 5.1 mm Hg, and there were no signs of left ventricular outflow tract obstruction (mean gradient 2.0 mm Hg). CONCLUSIONS: The 1-year results from the HighLife TSMVR feasibility study demonstrate a high technical success rate, excellent valve function, no left ventricular outflow tract obstruction, and no need for mitral valve reintervention. Additional patient outcomes and longer follow-up are needed to confirm these findings. (Expanded Study of the HighLife 28mm Trans-Septal Trans-Catheter Mitral Valve in Patients With Moderate-Severe or Severe Mitral Regurgitation and at High Surgical Risk; NCT04029363).

The COBRA II (COmplex Bifurcation lesions: RAndomized comparison of a fully bioresorbable modified-T stenting strategy versus bifurcation reconstruction with a dedicated self-expanding stent in combination with bioresorbable scaffolds) study: Final 5-year follow-up.

BACKGROUND: In order to advocate further research in bioresorbable scaffold (BVS) technology we report the final 5-year outcomes of the COBRA II study, the only randomized controlled trial (RCT) performed to investigate the safety, feasibility, and performance of Absorb BVS (Abbott Vascular) in true coronary bifurcations. METHODS: COBRA II was a prospective single-center RCT. Fifteen patients with true coronary bifurcation lesions were randomized to bifurcation treatment with self-expanding biolimus-eluting Axxess bifurcation device (Biosensors International) combined with additional bioresorbable everolimus-eluting Absorb BVS in the bifurcation branches on (Axxess group) or to 2-stent mod-T stenting technique with Absorb BVS (mod-T group). Optical coherence tomography was performed post-procedure and at 30-months. The primary endpoint was change in minimal luminal area (MLA) on OCT from baseline to 30-months. RESULTS: Fifteen patients with coronary bifurcation lesions were randomized to the Axxess group (n = 8) or Modified-T group (n = 7). At 30 months, MLAs were significantly smaller than post-procedure in the majority of bifurcation segments treated with BVS due to neointima formation, while MLAs in the proximal Axxess segment remained stable (primary endpoint). Five-year clinical follow-up was available for all patients. Only 1 major adverse cardiac event occurred; a patient underwent target lesion revascularization at 30 months in the Axxess group. There were no cases of cardiac death, spontaneous MI, or stent/scaffold thrombosis. CONCLUSIONS: In this small RCT bifurcation study, BVS luminal dimensions were significantly smaller at 30 months, with acute strut discontinuities and late Intraluminal dismantling frequently observed, although acceptable clinical outcomes were noted at 5 years.

Periprocedural continuation versus interruption of oral anticoagulant drugs during transcatheter aortic valve implantation: rationale and design of the POPular PAUSE TAVI trial.

About one-third of patients undergoing transcatheter aortic valve implantation (TAVI) use oral anticoagulants (OAC), mainly due to atrial fibrillation. General guidelines advise interrupting OAC in patients with a high risk of bleeding undergoing interventions. However, preliminary observational data suggest that the continuation of OAC during TAVI is safe and may reduce the risk of periprocedural thromboembolic events. The Periprocedural Continuation Versus Interruption of Oral Anticoagulant Drugs During Transcatheter Aortic Valve Implantation (POPular PAUSE TAVI) is a multicentre, randomised clinical trial with open-label treatment and blinded endpoint assessment. Patients are randomised 1:1 to periprocedural continuation versus interruption of OAC and are stratified for vitamin K antagonist or direct oral anticoagulant use. The primary endpoint is a composite of cardiovascular mortality, all stroke, myocardial infarction, major vascular complications and type 2-4 bleeding within 30 days after TAVI, according to the Valve Academic Research Consortium-3 criteria. Secondary endpoints include separate individual and composite outcomes, quality of life and cost-effectiveness. Since continuation of OAC is associated with the ancillary benefit that it simplifies periprocedural management, the primary outcome is first analysed for non-inferiority; if non-inferiority is proven, superiority will be tested. Recruitment started in November 2020, and the trial will continue until a total of 858 patients have been included and followed for 90 days. In summary, POPular PAUSE TAVI is the first randomised clinical trial to assess the safety and efficacy of periprocedural continuation versus interruption of OAC in patients undergoing TAVI.

A single mild juvenile TBI in male mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age.

Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.