Fitusiran reduces bleeding in factor X-deficient mice.

ABSTRACT: Factor X (FX) deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aim to explore the use of fitusiran (an investigational small interfering RNA 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 with control f10WT mice, f10low mice had sixfold and fourfold prolonged clotting times in prothrombin time and activated partial prothrombin time assays, respectively (P < .001). Thrombin generation was severely reduced, irrespective of whether tissue factor or factor XIa was used as an initiator. In vivo analysis revealed near-absent thrombus formation in a laser-induced vessel injury model. Furthermore, in 2 distinct bleeding models, f10low mice displayed an increased bleeding tendency compared with f10WT mice. In the tail-clip assay, blood loss was increased from 12 ± 16 µL to 590 ± 335 µL (P < .0001). In the saphenous vein puncture (SVP) model, the number of clots generated was reduced from 19 ± 5 clots every 30 minutes for f10WT mice to 2 ± 2 clots every 30 minutes (P < .0001) for f10low mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low mice with fitusiran (2 × 10 mg/kg at 1 week interval) resulted in 17 ± 6% residual antithrombin activity and increased thrombin generation (fourfold and twofold to threefold increase in endogenous thrombin potential and thrombin peak, respectively). In the SVP model, the number of clots was increased to 8 ± 6 clots every 30 minutes (P = .0029). Altogether, we demonstrate that reduction in antithrombin levels is associated with improved hemostatic activity under conditions of FX deficiency.

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.

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.

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.

DNAse-dependent, NET-independent pathway of thrombus formation in vivo.

The contribution of NETs (neutrophil extracellular traps) to thrombus formation has been intensively documented in both arterial and venous thrombosis in mice. We previously demonstrated that adenosine triphosphate (ATP)-activated neutrophils play a key role in initiating the tissue factor-dependent activation of the coagulation cascade, leading to thrombus formation following laser-induced injury. Here, we investigated the contribution of NETs to thrombus formation in a laser-induced injury model. In vivo, treatment of mice with DNase-I significantly inhibited the accumulation of polymorphonuclear neutrophils at the site of injury, neutrophil elastase secretion, and platelet thrombus formation within seconds following injury. Surprisingly, electron microscopy of the thrombus revealed that neutrophils present at the site of laser-induced injury did not form NETs. In vitro, ATP, the main neutrophil agonist present at the site of laser-induced injury, induced the overexpression of PAD4 and CitH3 but not NETosis. However, compared to no treatment, the addition of DNase-I was sufficient to cleave ATP and adenosine diphosphate (ADP) in adenosine. Human and mouse platelet aggregation by ADP and neutrophil activation by ATP were also significantly reduced in the presence of DNase-I. We conclude that following laser-induced injury, neutrophils but not NETs are involved in thrombus formation. Treatment with DNase-I induces the hydrolysis of ATP and ADP, leading to the generation of adenosine and the inhibition of thrombus formation in vivo.

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS: We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriate indications. Patients were assigned before TAVI in a 1:1 ratio not to receive clopidogrel or to receive clopidogrel for 3 months. The two primary outcomes were all bleeding and non-procedure-related bleeding over a period of 12 months. Procedure-related bleeding was defined as Bleeding Academic Research Consortium type 4 severe bleeding, and therefore most bleeding at the puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction at 12 months (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2), both tested for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: Bleeding occurred in 34 of the 157 patients (21.7%) receiving oral anticoagulation alone and in 54 of the 156 (34.6%) receiving oral anticoagulation plus clopidogrel (risk ratio, 0.63; 95% confidence interval [CI], 0.43 to 0.90; P = 0.01); most bleeding events were at the TAVI access site. Non-procedure-related bleeding occurred in 34 patients (21.7%) and in 53 (34.0%), respectively (risk ratio, 0.64; 95% CI, 0.44 to 0.92; P = 0.02). Most bleeding occurred in the first month and was minor. A secondary composite 1 event occurred in 49 patients (31.2%) receiving oral anticoagulation alone and in 71 (45.5%) receiving oral anticoagulation plus clopidogrel (difference, -14.3 percentage points; 95% CI for noninferiority, -25.0 to -3.6; risk ratio, 0.69; 95% CI for superiority, 0.51 to 0.92). A secondary composite 2 event occurred in 21 patients (13.4%) and in 27 (17.3%), respectively (difference, -3.9 percentage points; 95% CI for noninferiority, -11.9 to 4.0; risk ratio, 0.77; 95% CI for superiority, 0.46 to 1.31). CONCLUSIONS: In patients undergoing TAVI who were receiving oral anticoagulation, the incidence of serious bleeding over a period of 1 month or 1 year was lower with oral anticoagulation alone than with oral anticoagulation plus clopidogrel. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. METHODS: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. CONCLUSIONS: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Unravelling the Fate of Coronary Artery Disease in Patients Undergoing Valve Replacement for Severe Aortic Valve Stenosis.

Severe aortic valve stenosis is the most frequent valve pathology in the western world and approximately 50% of these patients have concomitant coronary artery disease (CAD). Revascularization of proximal obstructive CAD in patients undergoing surgical aortic valve replacement (SAVR) is common practice considered appropriate. However, the management of patients with CAD undergoing transcatheter aortic valve implantation (TAVI) is more controversial. Nevertheless, performing percutaneous coronary intervention (PCI) of significant ( > 70%) proximal coronary lesions is a widely adopted strategy, but robust supporting scientific evidence is missing. Some studies suggest that complex CAD with incomplete revascularization negatively impacts outcomes post-TAVI. As increasingly younger patients are undergoing TAVI, optimizing the long-term outcomes will become more important. Although PCI in TAVI patients is safe, no benefit on outcomes has been demonstrated, possibly due to an inadequate selection of prognostically important lesions for revascularization. A possible solution might be the use of coronary physiological indices, but these have their own limitations and more data is needed to support widespread adoption. In this review we provide an overview of current evidence on the outcomes after aortic valve replacement (AVR) and the evidence regarding revascularization in this population.

Heart Failure-Related Outcomes in Patients with Left Ventricular Dysfunction Undergoing Percutaneous Chronic Total Occlusion Revascularization.

Background: The presence of a chronic total occlusion (CTO) and severe left ventricular (LV) systolic dysfunction are known negative prognostic factors in patients with coronary artery disease. Several studies have examined the effect of CTO revascularization on mortality, symptoms, occurrence of myocardial infarction (MI), and cardiac function in patients with normal or reduced LV function. However, the effect of CTO revascularization on heart failure-related events in patients with LV dysfunction, such as heart failure hospitalization (HFH), the occurrence of atrial fibrillation (AF), and a worsening renal function (WRF), has not yet been evaluated. To assess the success rate and safety of CTO percutaneous coronary interventions (PCIs) in coronary patients with LV ejection fractions of ≤ 40% and evaluate the impact of successful CTO revascularization on HFH, occurrence of AF, and WRF. Methods: Prospectively, data were collected from CTO PCIs performed at three referral centers and analyzed. From a total of 1435 CTO PCIs, 132 (9.2%) patients with a left ventricular ejection fraction (LVEF) of ≤ 40% were included in this analysis. The median follow-up duration was 23.18 months (interquartile range (IQR): 11.02-46.66 months). Results: A successful CTO PCI was achieved in 109 of these patients, while the procedure was unsuccessful in 23 patients (82.5% procedural success rate). Overall, the intervention had an acceptable number of peri-procedural (or in-hospital) complications (9.1%). During the follow-up period, the rates of all-cause death, cardiovascular death, and non-fatal MI were not significantly different between the two groups. The rates of HFH were significantly lower in the successful PCI group, while WRF and AF did not differ between successful and unsuccessful PCI groups. Successful PCI and higher estimated glomerular filtration rate (eGFR) were independent predictors of a lower risk of HFH, while prior stroke and diabetes were independent predictors of a higher risk of HFH. Conclusions: In patients with reduced LV systolic function (ejection fraction, EF ≤ 40%), CTO PCI is a safe and effective procedure and successful CTO PCI is independently associated with a lower risk of HFH during follow-up. Further expansion of this cohort is necessary to confirm these results.

Final 36-Month Outcomes from the Multicenter DynamX Study Evaluating a Novel Thin-Strut Novolimus-Eluting Coronary Bioadaptor System and Supporting Preclinical Data.

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 mm 2 at baseline to 8.46 ± 1.31 mm 2 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.

Practical Approach to Transcatheter Aortic Valve Implantation and Bioprosthetic Valve Fracture in a Failed Bioprosthetic Surgical Valve.

Bioprosthetic surgical aortic valve failure requiring reintervention is a frequent clinical problem with event rates up to 20% at 10 years after surgery. Transcatheter aortic valve-in-valve implantation (ViV-TAVI) has become a valuable treatment option for these patients, although it requires careful procedural planning. We here describe and illustrate a stepwise approach to plan and perform ViV-TAVI and discuss preprocedural computerized tomography planning, transcatheter heart valve selection, and implantation techniques. Particular attention is paid to coronary artery protection and the possible need for bioprosthetic valve fracture since patients with small surgical aortic bioprostheses are at a risk of high residual gradients after ViV-TAVI. Considering updated clinical data on long-term outcomes following ViV-TAVI, this approach may become the default treatment strategy for patients with a failing surgical aortic bioprosthesis.

How to implement geriatric co-management in your hospital? Insights from the G-COACH feasibility study.

BACKGROUND: Geriatric co-management is advocated to manage frail patients in the hospital, but there is no guidance on how to implement such programmes in practice. This paper reports our experiences with implementing the 'Geriatric CO-mAnagement for Cardiology patients in the Hospital' (G-COACH) programme. We investigated if G-COACH was feasible to perform after the initial adoption, investigated how well the implementation strategy was able to achieve the implementation targets, determined how patients experienced receiving G-COACH, and determined how healthcare professionals experienced the implementation of G-COACH. METHODS: A feasibility study of the G-COACH programme was performed using a one-group experimental study design. G-COACH was previously implemented on two cardiac care units. Patients and healthcare professionals participating in the G-COACH programme were recruited for this evaluation. The feasibility of the programme was investigated by observing the reach, fidelity and dose using registrations in the electronic patient record and by interviewing patients. The success of the implementation reaching its targets was evaluated using a survey that was completed by 48 healthcare professionals. The experiences of 111 patients were recorded during structured survey interviews. The experiences of healthcare professionals with the implementation process was recorded during 6 semi-structured interviews and 4 focus groups discussions (n = 27). RESULTS: The programme reached 91% in a sample of 151 patients with a mean age of 84 years. There was a high fidelity for the major components of the programme: documentation of geriatric risks (98%), co-management by specialist geriatrics nurse (95%), early rehabilitation (80%), and early discharge planning (74%), except for co-management by the geriatrician (32%). Both patients and healthcare professionals rated G-COACH as acceptable (95 and 94%) and feasible (96 and 74%). The healthcare professionals experienced staffing, competing roles and tasks of the geriatrics nurse and leadership support as important determinants for implementation. CONCLUSIONS: The implementation strategy resulted in the successful initiation of the G-COACH programme. G-COACH was perceived as acceptable and feasible. Fidelity was influenced by context factors. Further investigation of the sustainability of the programme is needed. TRIAL REGISTRATION: ISRCTN22096382 (21/05/2020).

Study protocol for a pragmatic cluster randomized controlled trial to improve dietary diversity and physical fitness among older people who live at home (the "ALAPAGE study").

BACKGROUND: Diet and physical activity are key components of healthy aging. Current interventions that promote healthy eating and physical activity among the elderly have limitations and evidence of French interventions' effectiveness is lacking. We aim to assess (i) the effectiveness of a combined diet/physical activity intervention (the "ALAPAGE" program) on older peoples' eating behaviors, physical activity and fitness levels, quality of life, and feelings of loneliness; (ii) the intervention's process and (iii) its cost effectiveness. METHODS: We performed a pragmatic cluster randomized controlled trial with two parallel arms (2:1 ratio) among people ≥60 years old who live at home in southeastern France. A cluster consists of 10 people participating in a "workshop" (i.e., a collective intervention conducted at a local organization). We aim to include 45 workshops randomized into two groups: the intervention group (including 30 workshops) in the ALAPAGE program; and the waiting-list control group (including 15 workshops). Participants (expected total sample size: 450) will be recruited through both local organizations' usual practices and an innovative active recruitment strategy that targets hard-to-reach people. We developed the ALAPAGE program based on existing workshops, combining a participatory and a theory-based approach. It includes a 7-week period with weekly collective sessions supported by a dietician and/or an adapted physical activity professional, followed by a 12-week period of post-session activities without professional supervision. Primary outcomes are dietary diversity (calculated using two 24-hour diet recalls and one Food Frequency Questionnaire) and lower-limb muscle strength (assessed by the 30-second chair stand test from the Senior Fitness Test battery). Secondary outcomes include consumption frequencies of main food groups and water/hot drinks, other physical fitness measures, overall level of physical activity, quality of life, and feelings of loneliness. Outcomes are assessed before the intervention, at 6 weeks and 3 months later. The process evaluation assesses the fidelity, dose, and reach of the intervention as its causal mechanisms (quantitative and qualitative data). DISCUSSION: This study aims to improve healthy aging while limiting social inequalities. We developed and evaluated the ALAPAGE program in partnership with major healthy aging organizations, providing a unique opportunity to expand its reach. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05140330 , December 1, 2021. PROTOCOL VERSION: Version 3.0 (November 5, 2021).

Role of Neutrophils and NETs in Animal Models of Thrombosis.

Thrombosis is one of the major causes of mortality worldwide. Notably, it is not only implicated in cardiovascular diseases, such as myocardial infarction (MI), stroke, and pulmonary embolism (PE), but also in cancers. Understanding the cellular and molecular mechanisms involved in platelet thrombus formation is a major challenge for scientists today. For this purpose, new imaging technologies (such as confocal intravital microscopy, electron microscopy, holotomography, etc.) coupled with animal models of thrombosis (mouse, rat, rabbit, etc.) allow a better overview of this complex physiopathological process. Each of the cellular components is known to participate, including the subendothelial matrix, the endothelium, platelets, circulating cells, and, notably, neutrophils. Initially known as immune cells, neutrophils have been considered to be part of the landscape of thrombosis for more than a decade. They participate in this biological process through their expression of tissue factor (TF) and protein disulfide isomerase (PDI). Moreover, highly activated neutrophils are described as being able to release their DNA and thus form chromatin networks known as "neutrophil extracellular traps" (NETs). Initially, described as "dead sacrifices for a good cause" that prevent the dissemination of bacteria in the body, NETs have also been studied in several human pathologies, such as cardiovascular and respiratory diseases. Many articles suggest that they are involved in platelet thrombus formation and the activation of the coagulation cascade. This review presents the models of thrombosis in which neutrophils and NETs are involved and describes their mechanisms of action. We have even highlighted the medical diagnostic advances related to this research.

Neutrophils, Cancer and Thrombosis: The New Bermuda Triangle in Cancer Research.

Spontaneous venous thrombosis is often the first clinical sign of cancer, and it is linked to a worsened survival rate. Traditionally, tumor-cell induced platelet activation has been the main actor studied in cancer-associated-thrombosis. However, platelet involvement alone does not seem to be sufficient to explain this heightened pro-thrombotic state. Neutrophils are emerging as key players in both thrombus generation and cancer progression. Neutrophils can impact thrombosis through the release of pro-inflammatory cytokines and expression of molecules like P-selectin and Tissue Factor (TF) on their membrane and on neutrophil-derived microvesicles. Their role in cancer progression is evidenced by the fact that patients with high blood-neutrophil counts have a worsened prognosis. Tumors can attract neutrophils to the cancer site via pro-inflammatory cytokine secretions and induce a switch to pro-tumoral (or N2) neutrophils, which support metastatic spread and have an immunosuppressive role. They can also expel their nuclear contents to entrap pathogens forming Neutrophil Extracellular Traps (NETs) and can also capture coagulation factors, enhancing the thrombus formation. These NETs are also known to have pro-tumoral effects by supporting the metastatic process. Here, we strived to do a comprehensive literature review of the role of neutrophils as drivers of both cancer-associated thrombosis (CAT) and cancer progression.

The coronary and microcirculatory measurements in patients with aortic valve stenosis study: rationale and design.

Although concomitant coronary artery disease (CAD) is frequent in patients with severe aortic stenosis (AS), hemodynamic assessment of CAD severity in patients undergoing valve replacement for severe AS is challenging. Myocardial hypertrophic remodeling interferes with coronary blood flow and may influence the values of fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). The aim of the current study is to investigate the effect of the AS and its treatment on current indices used for evaluation of CAD. We will compare intracoronary hemodynamics before, immediately after, and 6 mo after aortic valve replacement (AVR) when it is expected that microvascular function has improved. Furthermore, we will compare FFR and resting full-cycle ratio (RFR) with myocardial perfusion single-photon emission-computed tomography (SPECT) as indicators of myocardial ischemia in patients with AS and CAD. One-hundred consecutive patients with AS and intermediate CAD will be prospectively included. Patients will undergo pre-AVR SPECT and intracoronary hemodynamic assessment at baseline, immediately after valve replacement [if transcatheter AVR (TAVR) is chosen], and 6 mo after AVR. The primary end point is the change in FFR 6 mo after AVR. Secondary end points include the acute change of FFR after TAVR, the diagnostic accuracy of FFR versus RFR compared with SPECT for the assessment of ischemia, changes in microvascular function as assessed by the index of microcirculatory resistance (IMR), and the effect of these changes on FFR. The present study will evaluate intracoronary hemodynamic parameters before, immediately after, and 6 mo after AVR in patients with AS and intermediate coronary stenosis. The understanding of the impact of AVR on the assessment of FFR, NHPR, and microvascular function may help guide the need for revascularization in patients with AS and CAD planned for AVR.

Contemporary Strategies and Outcomes of Dedicated Chronic Total Occlusion Percutaneous Coronary Intervention Programs: A Prospective Multicentre Registry.

BACKGROUND: The field of CTO PCI is expanding, but successful and safe percutaneous coronary intervention (PCI) of coronary chronic total occlusions (CTO) requires a substantial resource and experience investment. We aimed to assess temporal trends in strategies and outcomes of 2 dedicated programs for CTO PCI. METHODS: Between 2011 and 2020, 920 CTO PCI procedures were prospectively included at 2 referral centres in Belgium. Temporal trends were assessed, and logistic regression models were built to identify predictors of outcome. RESULTS: Despite an increase in lesion complexity (the J-CTO score increased from 1.3 in year 1 to 1.7-2.0 in years 8-9, p < 0.001), technical success improved from 70.0% to 85.6% in year 9 (p value for trend <0.001). We observed the most significant improvement starting at years 3-4 (OR 2.3 in year 4 versus year 1, p=0.018). Together with an increase in success rates and lesions complexity, there was an increase in the use of dual injections, retrograde approaches, the number of balloons and stents, and the use of microcatheters. Conversely, there was a decrease in large bore access, an increase in radial approach, and a shift towards contemporary dissection/reentry techniques. This strategy resulted in a stable major complication rate of 4.7% (p value for trend 0.33). The rate of coronary procedure-related myocardial injury was high (71.0%) and was associated with the use of more intracoronary devices. CONCLUSIONS: Three to four years after initiation of a dedicated CTO PCI program with 50 CTO PCIs per year, consistent high technical success and low complication rates are achieved using contemporary strategies.

Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence.

Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it has become evident that EV formation, secretion and uptake represent important mechanisms of intercellular communication and exchange of a wide variety of molecules, with relevance in both physiological and pathological situations. The putative role of EVs in hemostasis and thrombosis is supported by clinical and experimental studies unraveling how these cell-derived structures affect clot formation (and resolution). From those studies, it has become clear that the prothrombotic effects of EVs are not restricted to the exposure of tissue factor (TF) and phosphatidylserines (PS), but also involve multiplication of procoagulant surfaces, cross-linking of different cellular players at the site of injury and transfer of activation signals to other cell types. Here, we summarize the existing and novel clinical and experimental evidence on the role and function of EVs during arterial and venous thrombus formation and how they may be used as biomarkers as well as therapeutic vectors.

Industrially processed v. home-prepared dishes: what economic benefit for the consumer?

OBJECTIVE: To cope with the pressure of modern life, consumer demand for convenience foods has increased in the last decades. The current study set out to compare the costs of buying industrially processed dishes and of preparing them at home. DESIGN: Direct purchase costs of industrially processed dishes frequently consumed in France (n 19) and of the ingredients needed for their home-prepared counterparts (n 86) were collected from four major food retailers' websites in Montpellier, France. Mean prices and energy density were calculated for four portions. Costs related to energy used by cooking appliances and time spent preparing dishes were further estimated. SETTING: Montpellier, France. PARTICIPANTS: Not applicable. RESULTS: Based on the costs of ingredients and energy used for cooking, dishes prepared at home cost less (-0·60 € per four portions, P < 0.001) than industrially processed dishes, but when the cost of time was taken into account, the industrially processed dishes were much cheaper (-5·34 € per four portions, P < 0.001) than their home-prepared counterparts. There was no difference in energy density between industrially processed and home-prepared dishes. CONCLUSIONS: Our findings suggest that industrially processed dishes are more profitable to consumers when the cost of time for preparing dishes at home is valued. Given the ever greater demands of everyday life, more account should be taken of the additional cost to consumers of the time they spend preparing meals at home.