Laboratory for Vascular Translational Science

The 2023 Duke-ISCVID (International Society of Cardiovascular Infectious Diseases) classification is a new diagnostic tool for infective endocarditis, updating the 2000 modified Duke and the 2015 European Society for Cardiology (ESC) classifications. In comparison, its sensitivity is higher; however, its specificity remains to be evaluated and compared to that of the 2 other classifications in endocarditis suspected patients. We retrospectively collected the characteristics of patients hospitalized in Bichat University's Hospital, Paris, in 2021, who had been evaluated for clinical suspicion of endocarditis, have had at least a transthoracic echocardiography, 2 pairs of blood cultures, 3-month follow-up and in whom endocarditis diagnosis was finally rejected. All patients were classified by 2000 modified Duke, 2015 ESC and 2023 Duke-ISCVID, as though the endocarditis diagnosis had not been rejected. In total, 130 patients' charts were analyzed. Mean age was 62 years, 84 (64.6%) were male, 39 (30.0%) had prosthetic cardiac valve or valve repair, 21 (16.2%) cardiac implanted electronic device, and 30 (23.1%) other cardiac conditions. Overall, 5, 2, and 5 patients were falsely classified as definite endocarditis with the 2000 modified Duke, 2015 ESC, and 2023 Duke-ISCVID classifications, respectively. The corresponding specificities were 96.2% (95% confidence interval [CI] [90.8%, 98.6%]), 98.5% (95% CI [93.9%, 99.7%]), and 96.2% (95% CI [90.8%, 98.6%]). The rates of possible endocarditis were of 38%, 35%, and 35% in the 3 classifications, respectively. The 2023 Duke-ISCVID classification is highly specific for ruling out the diagnosis of definite infective endocarditis in patients who had been evaluated for IE.

This observational study aimed to evaluate Association pour l'Etude et la Prévention de l'Endocardite Infectieuse (AEPEI) surgery score predictive performance in comparison to general (EuroSCORE I, II) and specific (De Feo, PALSUSE) surgical risk scores for infective endocarditis (IE). The study included patients who underwent surgery for IE during the acute phase at Bichat University Hospital (Paris, France) between 1 January 2006 and 31 December 2016 and at Nancy University Hospital (Nancy, France) between 1 January 2009 and 31 December 2019. Patients with IE complicating percutaneous aortic valve implantations or implantable intra-cardiac devices were excluded. Discrimination and calibration were assessed using receiver operating characteristic curve analysis, calibration curves and the Hosmer-Lemeshow test. In-hospital mortality rates were 18% at Bichat and 16% at Nancy. Discrimination was high for all risk scores at Bichat (area under the receiver operating characteristic curve = 0.77 for EuroSCORE I, 0.78 for EuroSCORE II, 0.76 for De Feo score, 0.72 for PALSUSE and 0.73 for AEPEI with 95% confidence interval ranging from 0.67 to 0.83), but lower at Nancy (0.56 for EuroSCORE I, 0.65 for EuroSCORE II, 0.63 for De Feo score, 0.67 for PALSUSE and 0.66 for AEPEI score with 95% confidence interval ranging from 0.47 to 0.75). With Brier score, all scores were adequately calibrated in both populations between 0.129 (De Feo) and 0.135 (PALSUSE) for Bichat and between 0.128 (De Feo) and 0.135 (EuroSCORE I) for Nancy. With the Hosmer-Lemeshow test, the AEPEI score exhibited the best calibration (observed/predicted ratio 1.058 in Bichat, 1.087 in Nancy). This surgical score external validation in 2 large independent populations demonstrated that the AEPEI surgical score had the best predictive performance compared to other prognosis scores. It could be helpful in clinical practice to assist the endocarditis team in decision-making.

IgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression. Through histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression. Our data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

BackgroundThe first-pass, complete recanalization by mechanical thrombectomy (MT) for the treatment of large vessel occlusion remains limited. Currently, stent-retrievers come with a variety of different designs with the goal of better clot integration, but there are no coatings available that can attract elements of the clot. Co-aspiration techniques can help retrieval of the main clot, but does not always prevent distal emboli, or emboli to a new territory (ENT). Clot specimens retrieved with MT have been shown to have dense meshes of extracellular DNA (neutrophil extracellular traps: NETs) on histology. We hypothesized that stent retrievers modified with coatings that bind to NETs will reduce distal emboli by anchoring the clot to the device.MethodsNickel-titanium plates were coated with 15 different substrates. Extensive characterization of candidate coatings was performed including X-Ray Photoelectron Spectroscopy, Atomic Force Microscopy and ζ - potential measurement. The plates were then exposed to both NETs and human peripheral whole blood in vitro. The amount of chromatin and platelet binding was measured with immunohistochemistry. The two best candidate coatings were then applied to the Solitaire device and tested in a validated simulated use experiment of MCA occlusion. Briefly, an aged clot that was confirmed to have NETs was introduced into a vascular replica of the entire circle of Willis. The two coated devices and two control devices (bare metal stent and stent with only the base polydopamine (PDA) film) were block randomized for mechanical thrombectomy in the model with 10 replicate experiments for each device. All effluent was collected from the MCA and ACA territories separately for emboli analysis to the distal vasculature and ENT, respectively. We also measured the number of passes required to achieve complete recanalization.ResultsChromatin binding was increased with all compounds tested as compared to the bare metal alloy; however, the two best candidates were mustard benzo[b]furan (MBF) and a piperaquine derivative (Pipe-2) that showed a 3-fold and almost 2-fold affinity for chromatin, respectively. MBF and Pipe-2 also has reduced affinity for binding platelets compared to bare metal plates. These candidate compounds were tested in the simulated use experiment. The control devices had similar numbers of total fragmented emboli >200µm (bare metal: 55, PDA 49). Both candidate NETs binding coatings had a statistically significant reduction in total clot fragments released during MT as compared to the bare metal stent (MBF: 19; Pipe-2: 25; p=0.042). Although the final complete reperfusion was equivalent for all devices tested, in 70% of the thrombectomies the clot became dislodged from the bare metal stent in the ICA (which was then successfully aspirated). With the coating technologies, both MBF and Pipe-2, showed a dramatic reduction in the clot rolling off the stent, becoming dislodged in 20% or fewer of the MT procedures.ConclusionThese experiments have shown that coating technologies targeting NETs of clots causing large vessel occlusion lead to fewer clot fragments during stent-retriever thrombectomy. It was also observed that the clot ‘rolling’ off the surface of the stent was reduced with chromatin binding surface modification.DisclosuresV. Anagnostakou: None. C. Skarbek: None. M. Epshtein: None. E. Propocio: None. C. Raskett: None. R. Romagnoli: None. G. Iviglia: None. M. Morra: None. M. Antonucci: None. A. Nicoletti: 4; C; Kapto. G. Caligiuri: 4; C; Kapto. M. Gounis: 1; C; NIH, the United States – Israel Binational Science Foundation, Anaconda, ApicBio, Arsenal Medical, Axovant, Balt, Cerenovus, Ceretrieve, CereVasc LLC, Cook Medical, Galaxy Therapeutics, Gentuity, Gilb. 2; C; Alembic LLC, Astrocyte Pharmaceuticals, BendIt Technologies, Cerenovus, Imperative Care, Jacob’s Institute, Medtronic Neurovascular, Mivi Neurosciences, phenox GMbH, Q’Apel, Route 92 Medical, Scientia. 4; C; Imperative Care, InNeuroCo, Galaxy Therapeutics, Neurogami and Synchron.

Oligosaccharides derived from λ-carrageenan (λ-COs) are gaining interest in the cancer field. They have been recently reported to regulate heparanase (HPSE) activity, a protumor enzyme involved in cancer cell migration and invasion, making them very promising molecules for new therapeutic applications. However, one of the specific features of commercial λ-carrageenan (λ-CAR) is that they are heterogeneous mixtures of different CAR families, and are named according to the thickening-purpose final-product viscosity which does not reflect the real composition. Consequently, this can limit their use in a clinical applications. To address this issue, six commercial λ-CARs were compared and differences in their physiochemical properties were analyzed and shown. Then, a H2O2-assisted depolymerization was applied to each commercial source, and number- and weight-averaged molar masses (Mn and Mw) and sulfation degree (DS) of the λ-COs produced over time were determined. By adjusting the depolymerization time for each product, almost comparable λ-CO formulations could be obtained in terms of molar masses and DS, which ranged within previously reported values suitable for antitumor properties. However, when the anti-HPSE activity of these new λ-COs was screened, small changes that could not be attributed only to their small length or DS changes between them were found, suggesting a role of other features, such as differences in the initial mixture composition. Further structural MS and NMR analysis revealed qualitative and semi-quantitative differences between the molecular species, especially in the proportion of the anti-HPSE λ-type, other CARs types and adjuvants, and it also showed that H2O2-based hydrolysis induced sugar degradation. Finally, when the effects of λ-COs were assessed in an in vitro migration cell-based model, they seemed more related to the proportion of other CAR types in the formulation than to their λ-type-dependent anti-HPSE activity.

Prostanoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [701]) are activated by the endogenous ligands prostaglandins PGD2, PGE1, PGE2 , PGF2α, PGH2, prostacyclin [PGI2] and thromboxane A2. Differences and similarities between human and rodent prostanoid receptor orthologues, and their specific roles in pathophysiologic conditions are reviewed in [452]. Measurement of the potency of PGI2 and thromboxane A2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies.

Prone positioning and venovenous extracorporeal membrane oxygenation (ECMO) are both useful interventions in acute respiratory distress syndrome (ARDS). Combining the two therapies is feasible and safe, but the effectiveness is not known. Our objective was to evaluate the potential survival benefit of prone positioning in venovenous ECMO patients cannulated for COVID-19-related ARDS. Retrospective analysis of a multicenter cohort. Patients on venovenous ECMO who tested positive for severe acute respiratory syndrome coronavirus 2 by reverse transcriptase polymerase chain reaction or with a diagnosis on chest CT were eligible. None. All patients on venovenous ECMO for respiratory failure in whom prone position status while on ECMO and in-hospital mortality were known were included. Of 647 patients in 41 centers, 517 were included. Median age was 55 (47-61), 78% were male and 95% were proned before cannulation. After cannulation, 364 patients (70%) were proned and 153 (30%) remained in the supine position for the whole ECMO run. There were 194 (53%) and 92 (60%) deaths in the prone and the supine groups, respectively. Prone position on ECMO was independently associated with lower in-hospital mortality (odds ratio = 0.49 [0.29-0.84]; p = 0.010). In 153 propensity score-matched pairs, mortality rate was 49.7% in the prone position group versus 60.1% in the supine position group (p = 0.085). Considering only patients alive at decannulation, propensity-matched proned patients had a significantly lower mortality rate (22.4% vs 37.8%; p = 0.029) than nonproned patients. Prone position may be beneficial in patients supported by venovenous ECMO for COVID-19-related ARDS but more data are needed to draw definitive conclusions.