Publications by authors named "Christophe Dubois"

167 Publications

Clinical and Hemodynamic Effects of Percutaneous Edge-to-Edge Mitral Valve Repair in Atrial Versus Ventricular Functional Mitral Regurgitation.

Am J Cardiol 2021 12;161:70-75

Dept of Cardiology, Hospital Oost-Limburg, Genk, Belgium.

The present study aims to assess the clinical and hemodynamic impact of percutaneous edge-to-edge mitral valve repair with MitraClip in patients with atrial functional mitral regurgitation (A-FMR) compared with ventricular functional mitral regurgitation (V-FMR). Mitral regurgitation (MR) grade, functional status (New York Heart Association class), and major adverse cardiac events (MACE; all-cause mortality or hospitalization for heart failure) were evaluated in 52 patients with A-FMR and in 307 patients with V-FMR. In 56 patients, hemodynamic assessment during exercise echocardiography was performed before and 6 months after intervention. MR reduction after MitraClip implantation was noninferior in A-FMR compared with V-FMR (MR grade ≤2 at 6 months in 94% vs 82%, respectively, p <0.001 for noninferiority) and was associated with improvement of functional status (New York Heart Association class ≤2 at 6 months in 90% vs 80%, respectively, p = 0.2). Hemodynamic assessment revealed that cardiac output at 6 months was higher in A-FMR at rest (5.1 ± 1.5 L/min vs 3.8 ± 1.5 L/min, p = 0.002) and during peak exercise (7.9 ± 2.4 L/min vs 6.1 ± 2.1 L/min, p = 0.02). In addition, the reduction in systolic pulmonary artery pressure at rest was more pronounced in A-FMR: Δ SPAP -13.1 ± 15.1 mm Hg versus -2.2 ± 13.3 mm Hg (p = 0.03). MACE rate at follow-up was significantly lower in A-FMR versus V-FMR, with an adjusted odds ratio of 0.46 (95% confidence interval 0.24 to 0.88), which was caused by a reduction in hospitalization for heart failure. In conclusion, percutaneous edge-to-edge mitral valve repair with MitraClip is at least as effective in A-FMR as in V-FMR in reducing MR. However, the hemodynamic improvement and reduction of MACE were significantly better in A-FMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2021.08.062DOI Listing
December 2021

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

Am J Physiol Heart Circ Physiol 2021 12 22;321(6):H1106-H1116. Epub 2021 Oct 22.

Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00541.2021DOI Listing
December 2021

P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers.

Front Oncol 2021 13;11:704945. Epub 2021 Sep 13.

Aix Marseille Univ, INSERM 1263, INRA 1260, Center for Cardiovascular and Nutrition Research (C2VN), Marseille, France.

Platelet function can be modified by cancer cells to support tumor growth, causing alterations in the delicate hemostatic equilibrium. Cancer-cell and platelet interactions are one of the main pillars of Trousseau's syndrome: a paraneoplastic syndrome with recurring and migrating episodes of thrombophlebitis. Altogether, this leads to a four-fold risk of thrombotic events in cancer patients, which in turn, portend a poor prognosis. We previously demonstrated that anti-P2RY12 drugs inhibit cancer-associated-thrombosis and formation of tumor metastasis in pancreatic cancer models. Here, we aimed to (1) compare the effects of aspirin and clopidogrel on pancreatic cancer prevention, (2) characterize the effects of clopidogrel (platelet P2RY12 inhibitor) on cancer-associated thrombosis and cancer growth , (3) determine the effect of P2RY12 across different digestive-tract cancers , and (4) analyze the expression pattern of P2RY12 in two different cancer types affecting the digestive system. Clopidogrel treatment resulted in better survival rates with smaller primary tumors and less metastasis than aspirin treatment. Clopidogrel was also more effective than aspirin at dissolving spontaneous endogenous thrombi in our orthotopic advanced cancer mouse model. P2RY12 expression gives pancreatic adenocarcinomas proliferative advantages. In conclusion, we propose the hypothesis that clopidogrel should be further studied to target and prevent Trousseau's syndrome; as well as diminish cancer growth and spread. However, more studies are required to determine the implicated pathways and effects of these drugs on cancer development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.704945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475274PMC
September 2021

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

Int J Mol Sci 2021 Aug 27;22(17). Epub 2021 Aug 27.

Department of Cardiology, Cardiology I, University Medical Center Mainz, D-55131 Mainz, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22179317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431093PMC
August 2021

Antithrombotic Treatment After Surgical and Transcatheter Heart Valve Repair and Replacement.

Front Cardiovasc Med 2021 5;8:702780. Epub 2021 Aug 5.

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

New antithrombotic drugs have been developed, new valve types have been designed and minimally invasive transcatheter techniques have emerged, making the choice of antithrombotic therapy after surgical or transcatheter heart valve repair and replacement increasingly complex. Moreover, due to a lack of large randomized controlled trials many recommendations for antithrombotic therapy are based on expert opinion, reflected by divergent recommendations in current guidelines. Therefore, decision-making in clinical practice regarding antithrombotic therapy for prosthetic heart valves is difficult, potentially resulting in sub-optimal patient treatment. This article compares the 2017 ESC/EACTS and 2020 ACC/AHA guidelines on the management of valvular heart disease and summarizes the available evidence. Finally, we established a convenient consensus on antithrombotic therapy after valve interventions based on over 800 annual cases of surgical and transcatheter heart valve repair and replacement and a multidisciplinary team discussion between the department of cardiovascular diseases and cardiac surgery of the University Hospitals Leuven, Belgium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.702780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375148PMC
August 2021

Transcatheter Edge-to-Edge Repair in Proportionate Versus Disproportionate Functional Mitral Regurgitation.

J Am Soc Echocardiogr 2021 Aug 11. Epub 2021 Aug 11.

Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Background: Functional mitral regurgitation (FMR) can be subclassified on the basis of its proportionality relative to left ventricular (LV) volume and function, indicating potential differences in underlying etiology. The aim of this study was to evaluate the association of FMR proportionality with FMR reduction, heart failure hospitalization and mortality after transcatheter edge-to-edge mitral valve repair (TEER).

Methods: This multicenter registry included 241 patients with symptomatic heart failure with reduced LV ejection fraction treated with TEER for moderate to severe or greater FMR. FMR proportionality was graded on preprocedural transthoracic echocardiography using the ratio of the effective regurgitant orifice area to LV end-diastolic volume. Baseline characteristics, follow-up transthoracic echocardiography, and 2-year clinical outcomes were compared between groups.

Results: Median LV ejection fraction, effective regurgitant orifice area and LV end-diastolic volume index were 30% (interquartile range [IQR], 25%-35%), 27 mm, and 107 mL/m (IQR, 90-135 mL/m), respectively. Median effective regurgitant orifice area/LV end-diastolic volume ratio was 0.13 (IQR, 0.10-0.18). Proportionate FMR (pFMR) and disproportionate FMR (dFMR) was present in 123 and 118 patients, respectively. Compared with patients with pFMR, those with dFMR had higher baseline LV ejection fractions (median, 32% [IQR, 27%-39%] vs 26% [IQR, 22%-33%]; P < .01). Early FMR reduction with TEER was more pronounced in patients with dFMR (odds ratio, 0.45; 95% CI, 0.28-0.74; P < .01) than those with pFMR, but not at 12 months (odds ratio, 0.93; 95% CI, 0.53-1.63; P = .80). Overall, in 35% of patients with initial FMR reduction after TEER, FMR deteriorated again at 1-year follow-up. Rates of 2-year all-cause mortality and heart failure hospitalization were 30% (n = 66) and 37% (n = 76), with no differences between dFMR and pFMR.

Conclusions: TEER resulted in more pronounced early FMR reduction in patients with dFMR compared with those with pFMR. Yet after initial improvement, FMR deteriorated in a substantial number of patients, calling into question durable mitral regurgitation reductions with TEER in selected patients. The proportionality framework may not identify durable TEER responders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.echo.2021.08.002DOI Listing
August 2021

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

Proc Natl Acad Sci U S A 2021 07;118(28)

Aix Marseille University, INSERM 1263, Institut National de la Recherche pour l'Agriculture, l'alimentation et l'Environnement (INRAE) 1260, Center for CardioVascular and Nutrition Research (C2VN), 13380 Marseille, France;

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2100561118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285961PMC
July 2021

GluN2D NMDA Receptors Gate Fear Extinction Learning and Interneuron Plasticity.

Front Synaptic Neurosci 2021 24;13:681068. Epub 2021 May 24.

Department of Cell Biology and Anatomy, LSU Health Sciences Center New Orleans, New Orleans, LA, United States.

The cerebellum is critically involved in the formation of associative fear memory and in subsequent extinction learning. Fear conditioning is associated with a long-term potentiation at both excitatory and inhibitory synapses onto Purkinje cells. We therefore tested whether fear conditioning unmasks novel forms of synaptic plasticity, which enable subsequent extinction learning to reset cerebellar circuitry. We found that fear learning enhanced GABA release from molecular layer interneurons and this was reversed after fear extinction learning. Importantly an extinction-like stimulation of parallel fibers after fear learning is sufficient to induce a lasting decrease in inhibitory transmission (I-LTD) in the cerebellar cortex, a form of plasticity that is absent in naïve animals. While NMDA (N-methyl-D-aspartate) receptors are required for the formation and extinction of associative memory, the role of GluN2D, one of the four major NMDA receptor subunits, in learning and memory has not been determined. We found that fear conditioning elevates spontaneous GABA release in GluN2D KO as shown in WT mice. Deletion of GluN2D, however, abolished the I-LTD induced by parallel fiber stimulation after learning. At the behavioral level, genetic deletion of GluN2D subunits did not affect associative learning and memory retention, but impaired subsequent fear extinction learning. D-cycloserine, a partial NMDA receptor (NMDAR) agonist, failed to rescue extinction learning in mutant mice. Our results identify GluN2D as a critical NMDAR subunit for extinction learning and reveal a form of GluN2D-dependent metaplasticity that is associated with extinction in the cerebellum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnsyn.2021.681068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183684PMC
May 2021

Geriatric co-management for cardiology patients in the hospital: A quasi-experimental study.

J Am Geriatr Soc 2021 05 17;69(5):1377-1387. Epub 2021 Mar 17.

Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Background/objectives: Older patients admitted to cardiac care units often suffer functional decline. We evaluated whether a nurse-led geriatric co-management program leads to better functional status at hospital discharge.

Design: A quasi-experimental before-and-after study was performed between September 2016 and December 2018, with the main endpoint at hospital discharge and follow-up at 6 months.

Setting: Two cardiac care units of the University Hospitals Leuven.

Participants: One hundred and fifty-one intervention and 158 control patients aged 75 years or older admitted for acute cardiovascular disease or transcatheter aortic valve implantation.

Intervention: A nurse from the geriatrics department performed a comprehensive geriatric assessment within 24 h of admission. The cardiac care team and geriatrics nurse drafted an interdisciplinary care plan, focusing on early rehabilitation, discharge planning, promoting physical activity, and preventing geriatric syndromes. The geriatrics nurse provided daily follow-up and coached the cardiac team. A geriatrician co-managed patients with complications.

Measurements: The primary outcome was functional status measured using the Katz Index for independence in activities of daily living (ADL; one-point difference was considered clinically relevant). Secondary outcomes included the incidence of ADL decline and complications, length of stay, unplanned readmissions, survival, and quality of life.

Results: The mean age of patients was 85 years. Intervention patients had better functional status at hospital discharge (8.9, 95% CI = 8.7-9.3 versus 9.5, 95% CI = 9.2-9.9; p = 0.019) and experienced 18% less functional decline during hospitalization (25% vs. 43%, p = 0.006). The intervention group experienced significantly fewer cases of delirium and obstipation during hospitalization, and significantly fewer nosocomial infections. At 6-month follow-up, patients had significantly better functional status and quality of life. There were no differences regarding length of stay, readmissions, or survival.

Conclusion: This first nurse-led geriatric co-management program for frail patients on cardiac care units was not effective in improving functional status, but significantly improved secondary outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.17093DOI Listing
May 2021

COmplex Bifurcation Lesions: RAndomized Comparison of Modified-T Stenting vs Reconstruction With Self-Expanding Stent and Bioresorbable Scaffold: COBRA II.

J Invasive Cardiol 2021 04 4;33(4):E281-E293. Epub 2021 Mar 4.

Department of Cardiovascular Medicine, University Hospitals Leuven, Herestraat 49, B 3000 Leuven, Belgium.

Objectives: To evaluate the role of a double bioresorbable vascular scaffold (BVS) strategy in coronary bifurcations, alone or in combination with a dedicated bifurcation device.

Methods: COBRA II is a prospective, single-center, randomized controlled trial. Patients were randomized to treatment with biolimus-eluting Axxess bifurcation device (Biosensors) in combination with Absorb BVS (Abbott Vascular) or a modified-T strategy using Absorb BVS. Optical coherence tomography (OCT) was performed post procedure and at 30 months. The primary endpoint was change in minimal luminal area (MLA) on OCT from baseline to 30-month follow-up. Clinical endpoints included major adverse cardiac event (MACE) rate.

Results: From February 2016 to February 2017, a total of 15 patients with complex coronary bifurcation lesions were randomized to Axxess (n = 8) or modified-T strategy (n = 7). Procedure success rate was 100%. At 30-month follow-up, MLAs were significantly smaller than post procedure in proximal main vessel (MV), ostial distal MV, and ostial side branch (SB) after modified-T (mean difference, -3.1 ± 1.3 mm² [P<.001]; -2.1 ± 1.0 mm² [P<.01]; -2.1 ± 1.4 mm² [P=.03], respectively) and in ostial distal MV and ostial SB after Axxess (-2.1 ± 0.8 mm² [P<.001]; -1.6 ± 0.7 mm² [P<.01], respectively), while in proximal Axxess segment, the MLA remained stable (-0.1 ± 0.0; P=.93) and significantly larger than modified-T, mainly due to a smaller neointimal area (1.8 ± 0.7 mm² vs 3.2 ± 0.6 mm²; P<.001). Acute BVS strut discontinuities were observed in 53%, and late intraluminal dismantling was seen in 38% of patients. At 3 years, 1 MACE and no scaffold thromboses were observed.

Conclusions: In this serial imaging bifurcation study, BVS luminal dimensions were significantly smaller at 30 months, with acute strut discontinuities and late Intraluminal dismantling frequently observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2021

Oral Squamous Cell Carcinoma Is Associated with a Low Thrombosis Risk Due to Storage Pool Deficiency in Platelets.

Biomedicines 2021 Feb 24;9(3). Epub 2021 Feb 24.

Aix Marseille Université, INSERM 1263, INRAE, C2VN, 13885 Marseille, France.

Venous thrombo-embolism (VTE) disease is the second most common cause of mortality in cancer patients, and evaluation and prevention of thrombosis risk is essential. VTE-associated risk varies according to the type of tumor disease. Oral cancer is the most frequent type of head and neck cancer, and it represents approximately 2.1% of all cancers worldwide. Most tumors are squamous cell carcinomas and are mainly due to tobacco and alcohol abuse. VTE risk associated with oral squamous cell carcinoma (OSCC) is low. However, many studies have shown that OSCC has the following biological features of cancers associated with a high thrombosis risk: modified thrombosis and fibrinolysis mechanisms; strong expression of procoagulant proteins; secretion of procoagulant microparticles; and production of procoagulant cytokines. Using an original mouse model of tongue squamous cell carcinoma, our study aimed to clarify this paradoxical situation. First, we showed that OSCC tumors have a pro-aggregatory phenotype and a high local thrombosis risk. Second, we found that tongue tumor mice do not have an elevated systemic thrombosis risk (the risk of an "at distance" thrombosis event such as lower extremity deep venous thrombosis or pulmonary embolism) and even show a reduction in risk. Third, we demonstrated that tongue tumor mice show a reduction in platelet reactivity, which explains the low systemic thrombosis risk. Finally, we found that tongue tumor mice present granule pool deficiency, thereby explaining the reduction in platelet reactivity and systemic thrombosis risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9030228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996194PMC
February 2021

Left Impella®-device as bridge from cardiogenic shock with acute, severe mitral regurgitation to MitraClip®-procedure: a new option for critically ill patients.

Eur Heart J Acute Cardiovasc Care 2021 May;10(4):415-421

Department of Adult Intensive Care, Royal Brompton and Harefield NHS Foundation Trust, Sydney St, Chelsea, London SW3 6NP, UK.

Aims: Patients presenting with cardiogenic shock (CS) related to acute, severe mitral regurgitation (MR) are often considered too ill for immediate surgical intervention. Therefore, other less invasive techniques for haemodynamic stabilization should be explored. The purpose of this exploratory study was to investigate the feasibility and outcomes in patients with CS due to severe MR by using a novel approach combining haemodynamic stabilization with left Impella-support plus MR-reduction using MitraClip®.

Methods And Results: We analysed whether a combined left Impella®/MitraClip®-procedure in a rare population of CS-patients with acute MR requiring mechanical ventilation is a feasible strategy to recovery in patients who had been declined cardiac surgery. Six INTERMACS-1 CS-patients with acute MR were studied at two tertiary cardiac intensive care units. The mean EURO-II score was 39 ± 19% and age 66.8 ± 4.9 years. All patients had an initial pulmonary capillary wedge pressure >20 mmHg and pulmonary oedema necessitating invasive ventilation. Cardiac output was severely impaired (left ventricular outflow tract velocity time index 9.8 ± 1.8 cm), requiring mechanical circulatory support (MCS) (Impella®-CP; mean flow 2.9 ± 1.8 L per minute; mean support 9.7 ± 6.0 days). Despite MCS-guided unloading, weaning from ventilation failed due to persisting pulmonary oedema necessitating MR-reduction. In all cases, the severe MR was reduced to mild using percutaneous MitraClip®-procedure, followed by successful weaning from invasive ventilation. Survival to discharge was 86%, with all surviving and rare readmission for heart failure at 6 months.

Conclusions: A combined Impella®/MitraClip®-strategy appears a novel, feasible alternative for weaning CS-patients presenting with acute, severe MR. Upfront Impella®-stabilization facilitates safe bridging to Mitraclip®-procedure and the staged approach facilitates successful weaning from ventilatory support.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjacc/zuaa031DOI Listing
May 2021

Selatogrel, a reversible P2Y12 receptor antagonist, has reduced off-target interference with haemostatic factors in a mouse thrombosis model.

Thromb Res 2021 04 6;200:133-140. Epub 2021 Feb 6.

Aix Marseille Université, INSERM 1263, INRAE 1260 27 Boulevard Jean Moulin, Marseille, France.

Introduction: Selatogrel is a reversible antagonist of the P2Y12 receptor. In rat thrombosis/haemostasis models, selatogrel was associated with lower blood loss than clopidogrel or ticagrelor at equivalent anti-thrombotic effect.

Material And Methods: We sought to elucidate the mechanism underlying the observed differences in blood loss, using real-time intravital microscopy in mouse.

Results: Selatogrel, ticagrelor and clopidogrel dose-dependently inhibited laser-induced platelet thrombus formation. At maximal antithrombotic effect, only small mural platelets aggregates, corresponding to hemostatic seals, were present. The phenotype of these hemostatic seals was dependent on the type of P2Y12 receptor antagonist. In the presence of clopidogrel and ticagrelor, detachment of platelets from the hemostatic seals was increased, indicative of reduced stability. In contrast, in the presence of selatogrel, platelet detachment was not increased. Moreover, equivalent antithrombotic dosing regimens of ticagrelor and clopidogrel reduced laser-induced calcium mobilization in the endothelium, restricted neutrophil adhesion and subsequent fibrin formation and thus reduced fibrin-mediated stabilization of the hemostatic seals. The effects of ticagrelor were also observed in P2Y12 receptor deficient mice, indicating that the effects are off-target and independent of the P2Y12 receptor. In contrast, selatogrel did not interfere with these elements of haemostasis in wild-type or in P2Y12 receptor deficient mice.

Conclusion: In the presence of selatogrel the stability of hemostatic seals was unperturbed, translating to an improved blood loss profile. Our data suggest that the mechanism underlying the differences in blood loss profiles of P2Y12 receptor antagonists is by off-target interference with endothelial activation, neutrophil function and thus, fibrin-mediated stabilization of haemostatic seals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2021.01.026DOI Listing
April 2021

Author Correction: Inhibitory neurotransmission drives endocannabinoid degradation to promote memory consolidation.

Nat Commun 2021 Feb 8;12(1):987. Epub 2021 Feb 8.

Department of Cell Biology and Anatomy, LSU Health Sciences Center, New Orleans, LA, 70112, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21329-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870847PMC
February 2021

Inhibitory neurotransmission drives endocannabinoid degradation to promote memory consolidation.

Nat Commun 2020 12 17;11(1):6407. Epub 2020 Dec 17.

Department of Cell Biology and Anatomy, LSU Health Sciences Center, New Orleans, LA, 70112, USA.

Endocannabinoids retrogradely regulate synaptic transmission and their abundance is controlled by the fine balance between endocannabinoid synthesis and degradation. While the common assumption is that "on-demand" release determines endocannabinoid signaling, their rapid degradation is expected to control the temporal profile of endocannabinoid action and may impact neuronal signaling. Here we show that memory formation through fear conditioning selectively accelerates the degradation of endocannabinoids in the cerebellum. Learning induced a lasting increase in GABA release and this was responsible for driving the change in endocannabinoid degradation. Conversely, Gq-DREADD activation of cerebellar Purkinje cells enhanced endocannabinoid signaling and impaired memory consolidation. Our findings identify a previously unappreciated reciprocal interaction between GABA and the endocannabinoid system in which GABA signaling accelerates endocannabinoid degradation, and triggers a form of learning-induced metaplasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20121-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747732PMC
December 2020

Predictors of Mortality and Effect of Drug Therapies in Mechanically Ventilated Patients With Coronavirus Disease 2019: A Multicenter Cohort Study.

Crit Care Explor 2020 Dec 25;2(12):e0305. Epub 2020 Nov 25.

Department of Intensive Care, University Hospital of Liege, Liege, Belgium.

We conducted a multicenter cohort study to determine the effect of drug therapies on survival in mechanically ventilated patients with coronavirus disease 2019. All consecutive adult patients admitted to ICU for coronavirus disease 2019 from March 1, 2020, to April 25, 2020, and under invasive mechanical ventilation for more than 24 hours were included. Out of 2,003 patients hospitalized for coronavirus disease 2019, 361 were admitted to ICU, 257 were ventilated for more than 24 hours, and 247 were included in the study. Simple and multiple time-dependent Cox regression models were used to assess the effects of factors on survival. Methylprednisolone administration during the first week of mechanical ventilation was associated with a decrease in mortality rate from 48% to 34% ( = 0.01). Mortality was significantly associated with older age, higher creatinine, lower lymphocyte count, and mean arterial pressure lower than 70 mm Hg on the day of admission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCE.0000000000000305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690766PMC
December 2020

Efficacy of MAVIG X-Ray Protective Drapes in Reducing Operator Radiation Dose in the Cardiac Catheterization Laboratory: A Randomized Controlled Trial.

Circ Cardiovasc Interv 2020 11 23;13(11):e009627. Epub 2020 Oct 23.

Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium (K.M., M.V., R.P., J.B., T.A., C.D., P.S., W.D.).

Background: Interventional cardiologists are occupationally exposed to high doses of ionizing radiation. The MAVIG X-ray protective drape (MXPD) is a commercially available light weight, lead-free shield placed over the pelvic area of patients to minimize operator radiation dose. The aim of this study was to examine the efficacy of the MXPD during routine cardiac catheterization, including percutaneous coronary interventions.

Methods: We performed a prospective, randomized controlled study comparing operator radiation dose during cardiac catheterization and percutaneous coronary intervention (n=632) with or without pelvic MXPD. We measured operator radiation dose at 4 sites: left eye, chest, left ring finger, and right ring finger. The primary outcomes were the difference in first operator radiation dose (µSv) and relative dose of the first operator (radiation dose normalized for dose area product) at the level of the chest in the 2 groups.

Results: The use of the MXPD was associated with a 50% reduction in operator radiation dose (median dose 30.5 [interquartile range, 23.0-39.7] µSv in no drape group versus 15.3 [interquartile range, 11.1-20.0] µSv in the drape group; <0.001) and a 57% reduction in relative operator dose (<0.001). The largest absolute reduction in dose was observed at the left finger (median left finger dose for the no drape group was 104.9 [75.7-137.4] µSv versus 41.9 [32.6-70.6] µSv in the drape group; <0.001).

Conclusions: The pelvic MXPD significantly reduces first operator radiation dose during routine cardiac catheterization and percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04285944.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009627DOI Listing
November 2020

Twelve-month clinical and imaging outcomes of the uncaging coronary DynamX bioadaptor system.

EuroIntervention 2020 Dec 18;16(12):e974-e981. Epub 2020 Dec 18.

Interventional Cardiology, ZNA Cardiovascular Center Middelheim, Antwerp, Belgium.

Aims: We aimed to assess the safety and efficacy of the DynamX Novolimus-Eluting Coronary Bioadaptor System, a novel device that initially acts as a second-generation drug-eluting stent, but after six months frees the vessel through uncaging elements.

Methods And Results: This multicentre study enrolled 50 patients with single de novo lesions. In-device acute lumen gain was 1.61±0.34 mm, and device and procedure success was 100%. Up to 12 months, two target lesion failures occurred: both were cardiac deaths (day 255 and day 267 post procedure). No definite or probable device thrombosis was observed. Mean late lumen loss was 0.12±0.18 mm in-device and 0.11±0.16 mm in-segment. Per intravascular ultrasound, the mean device area and mean vessel area increased significantly by 5% and 3%, respectively, while the mean lumen area was maintained. Stationary optical coherence tomography in seven patients demonstrated restoration of cyclic pulsatility, with an approximate lumen area variance of 11% between systole and diastole.

Conclusions: The DynamX bioadaptor showed drug-eluting stent-like acute performance and safety and efficacy up to one year. Positive remodelling with an increase of vessel and device area while maintaining the mean lumen area was demonstrated. Long-term follow-up and randomised trials are required to assess the benefit of this device on events beyond one year.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4244/EIJ-D-20-00763DOI Listing
December 2020

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

N Engl J Med 2020 10 30;383(15):1447-1457. Epub 2020 Aug 30.

From the Department of Cardiology, St. Antonius Hospital, Nieuwegein (J. Brouwer, V.J.N., J.P., D.R.P.P.C.P.Y., M.J.S., B.J.W.M.R., L.T., J.C.K., J.M.B.), the Department of Cardiology, Amsterdam University Medical Center, Amsterdam (R.D., J. Baan), the Department of Cardiology, Isala Hospital, Zwolle (R.S.H.), the Department of Cardiology, Maastricht University Medical Center (W.H., L.V., A.W.J.H.) and the Cardiovascular Research Institute Maastricht (A.W.J.H., J.M.B.), Maastricht, the Department of Cardiology, Medisch Spectrum Twente, Enschede (G.K.H.), the Department of Cardiology, Leiden University Medical Center, Leiden (F.K.), the Department of Cardiology, Haga Hospital, The Hague (C.E.S.), the Department of Cardiology, University Medical Center Groningen, Groningen (P.H.), Erasmus School of Health Policy and Management, Erasmus University, Rotterdam (F.W.F.T.), the Department of Cardiology, Zuyderland Medical Center, Heerlen (A.W.J.H.), and the Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht (P.R.S.) - all in the Netherlands; the Department of Cardiology, University Hospital Leuven, Leuven (C.L.F.D.), Cardiovascular Center Aalst, Onze Lieve Vrouwe Clinic (B.D.B.), and the Department of Cardiology, Algemeen Stedelijk Hospital Aalst (I.B.), Aalst, the Department of Cardiology, Sint-Jan Hospital, Brugge (J.A.S.V.D.H.), the Department of Cardiology, Hospital Oost-Limburg, Genk (B.F.), and the Department of Cardiology, Imelda Hospital, Bonheiden (J.R.) - all in Belgium; the Department of Cardiology, Institut National de Chirurgie Cardiaque et de Cardiologie Interventionnelle, Luxembourg, Luxembourg (P.F.); and the Department of Cardiology, University Hospital Královské Vinohrady and Third Medical Faculty, Charles University, Prague, Czech Republic (P.T.).

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.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2017815DOI Listing
October 2020

Cancer animal models in thrombosis research.

Thromb Res 2020 07;191 Suppl 1:S112-S116

Aix Marseille University, INSERM 1263, INRAE, C2VN, Marseille, France. Electronic address:

The cancer-thrombosis relationship has been established for decades, in both cancer biology and in the clinical signs and symptoms seen in cancer patients (thrombosis in cancer patients has been associated with a worse prognosis and survival). As the link between the pathologies becomes clearer, so does the need to develop models that enable researchers to study them simultaneously in vivo. Mouse models have often been used, and they have helped determine molecular pathways between cancer spread and thrombosis in humans. This review is a summary of the current literature that describes the use of cancer mouse models in thrombosis research. We included cancer models that are not yet used in thrombosis research, but that can positively impact this area of research in the near future. We describe the most commonly used techniques to generate thrombosis as well as the mouse strains and cancer cell types that are commonly used along with inoculation techniques. We endeavoured to create a compendium of the different mouse models that are beneficial for cancer-thrombosis research, as understanding these mechanisms is crucial for creating better and more effective treatments for thrombosis in cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0049-3848(20)30407-2DOI Listing
July 2020

Nutritional Quality of Vegetarian and Non-Vegetarian Dishes at School: Are Nutrient Profiling Systems Sufficiently Informative?

Nutrients 2020 Jul 28;12(8). Epub 2020 Jul 28.

MOISA, Université de Montpellier, CIRAD, CIHEAM-IAMM, INRAE, Institut Agro, 34060 Montpellier, France.

In France, school canteens must offer a vegetarian meal at least once per week. The objective was to evaluate the nutritional quality of school main dishes. A database of main dishes served in primary schools was first split into non-vegetarian ( = 669) and vegetarian ( = 315) categories. The latter has been divided into three sub-categories: vegetarian dishes containing cheese, vegetarian dishes containing eggs and/or dairy products but no cheese and vegetarian dishes without any eggs, cheese or other dairy products (vegan). Categories and sub-categories were compared based on nutrient adequacy ratios for "protective" nutrients (proteins, fibres, vitamins, minerals, essential fatty acids), the contents of nutrients to be limited (saturated fatty acids (SFA), sodium, free sugars) and on two nutrient profiling systems (SAIN,LIM and Nutri-Score). The vegetarian category and the non-vegetarian category displayed "adequate" levels (≥5% adequacy for 100 kcal) on average for almost all "protective" nutrients. The three sub-categories of vegetarian dishes displayed good SAIN,LIM and Nutri-Score profiles on average, although key nutrients were lacking (vitamin B12, vitamin D and DHA) or were present in insufficient amounts (vitamin B2 and calcium) in the vegan sub-category. The sub-category containing eggs and/or dairy products other than cheese was a good compromise, as it provided protective nutrients associated with eggs and fresh dairy products, while the sub-category containing cheese provided higher levels of SFA. Nutrient profile algorithms are insufficiently informative to assess the nutritional quality of school dishes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12082256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468702PMC
July 2020

Heart team 2.0: A decision tree for minimally invasive and hybrid myocardial revascularization.

Trends Cardiovasc Med 2021 08 24;31(6):382-391. Epub 2020 Jul 24.

Department of Cardiovascular Diseases, Research Unit of Cardiac Surgery, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Recent years have seen an important shift in the target population for myocardial revascularization. Patients are increasingly presenting with more complex coronary artery disease (CAD), but also with multiple comorbidities and frailty. At the same time, minimally invasive strategies such as Minimally Invasive Direct Coronary Artery Bypass Grafting (MIDCAB) and Percutaneous Coronary Interventions (PCI) have been developed, which might be more appealing for this group of patients. As a result, the landscape of options for myocardial revascularization is evolving while adequate use of all resources is required to ensure optimal patient care. Heart Teams are confronted with the challenge of incorporating the new minimally invasive strategies into the decision process, yet current guidelines do not fully address this challenge. In this review, the current evidence regarding outcomes, indications, benefits, and risks of off-pump coronary artery bypass grafting (OPCAB), MIDCAB, PCI, and hybrid coronary revascularization (HCR) are discussed. Based on this evidence and on experiences from Heart Team discussions, a new decision tree is proposed that incorporates recent advances in minimally invasive revascularization strategies, thereby optimizing adequate delivery of care for each individual patient's needs. Introducing all important considerations in a logical way, this tool facilitates the decision-making process and might ensure appropriate use of resources and optimal care for individual patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcm.2020.07.005DOI Listing
August 2021

Perinatal exposure to ethanol in rats induces permanent disturbances of breathing and chemosensitivity during adulthood.

Neurosci Lett 2020 09 29;735:135219. Epub 2020 Jun 29.

UPJV, INSERM UMR 1247 GRAP, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Centre Universitaire de Recherche en Santé (CURS), Amiens Cedex 1, France.

Perinatal exposure to drugs of abuse, including alcohol (ethanol), is known to impinge the development of respiratory function. However, most studies described the short-term effects of these exposures, focusing mostly on the early postnatal life. After exposure to ethanol during gestation and lactation we have previously shown that 3-4 week-old rat exhibit chronic hypoventilation and an altered response to hypoxia at the end of ethanol exposure. However, whether these deficits are reversible following ethanol withdrawal remained unknown. Here, we investigated through whole-body plethysmography the respiratory activity of 2 months-old rats exposed to ethanol from gestation to weaning followed by one month of ethanol withdrawal. After ethanol withdrawal, rats persistently exhibited a significant reduction in respiratory frequency without change in tidal volume associated to a lower arterial blood oxygen content. In addition, the response to hypoxia in these rats was reduced whereas the response to hypercapnia remained unaltered. In conclusion perinatal exposure to ethanol in rats, unlike exposure to cocaine, morphine or nicotine, is characterized by selective alterations of basal respiratory activity and chemosensitivity that persist long after withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2020.135219DOI Listing
September 2020

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

Public Health Nutr 2020 08 27;23(11):1982-1990. Epub 2020 May 27.

MOISA, Univ Montpellier, CIRAD, CIHEAM-IAMM, INRAE, Institut Agro, Montpellier, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1368980019005081DOI Listing
August 2020

Assessment of Thrombotic and Bleeding Tendency in Two Mouse Models of Chronic Kidney Disease: Adenine-Diet and 5/6th Nephrectomy.

TH Open 2020 Apr 16;4(2):e66-e76. Epub 2020 Apr 16.

Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France.

The coexistence of bleeding and thrombosis in patients with chronic kidney disease (CKD) is frequent and poorly understood. Mouse models are essential to understand complications of CKD and to develop new therapeutic approaches improving the health of patients. We evaluated the hemostasis in two models of renal insufficiency: adenine-diet and 5/6th nephrectomy (5/6Nx). Compared with 5/6Nx mice, mice fed with 0.25% adenine had more severe renal insufficiency and so higher levels of prothrombotic uremic toxins like indoxyl sulfate. More severe renal inflammation and fibrosis were observed in the adenine group, as demonstrated by histological and reverse transcription quantitative polymerase chain reaction experiments. Liver fibrinogen γ chain expression and level of plasma fibrinogen were increased only in adenine mice. In both CKD mouse models, tissue factor (TF) expression was increased in kidney and aorta extracts. Immunochemistry analysis of kidney sections showed that TF is localized in the vascular walls. Thrombin-antithrombin complexes were significantly increased in plasma from both adenine and 5/6Nx mice. Tail bleeding time increased significantly only in adenine mice, whereas platelet count was not significant altered. Finally, results obtained by intravital microscopy after laser-induced endothelial injury showed impaired platelet function in adenine mice and an increase in fibrin generation in 5/6Nx mice. To summarize, adenine diet causes a more severe renal insufficiency compared with 5/6Nx. The TF upregulation and the hypercoagulable state were observed in both CKD models. Bleeding tendency was observed only in the adenine model of CKD that recapitulates the whole spectrum of hemostasis abnormalities observed in advanced human CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1705138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162676PMC
April 2020

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

N Engl J Med 2020 04 29;382(18):1696-1707. Epub 2020 Mar 29.

From the Department of Cardiology, St. Antonius Hospital, Nieuwegein (V.J.N., J. Brouwer, J.P., D.R.P.P.C.P.Y., M.J.S., B.J.W.M.R., L.T., J.C.K., J.M.B.), the Department of Cardiology, Amsterdam University Medical Centers, Location AMC, Amsterdam (R.D., J. Baan), the Department of Cardiology, Isala Hospital, Zwolle (R.S.H.), the Department of Cardiology, Maastricht University Medical Center and Cardiovascular Research Institute, Maastricht (W.H., L.V., A.W.J.H.), the Department of Cardiology, Medisch Spectrum Twente, Enschede (G.K.H.), the Department of Cardiology, Leiden University Medical Center, Leiden (F.K.), the Department of Cardiology, Haga Hospital, The Hague (C.E.S.), the Department of Cardiology, University Medical Center Groningen, Groningen (P.H.), Erasmus School of Health Policy and Management, Erasmus University, Rotterdam (F.W.F.T.), the Department of Cardiology, Zuyderland Medical Center, Heerlen (A.W.J.H.), and the Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht (P.R.S.) - all in the Netherlands; the Department of Cardiology, University Hospital Leuven, Leuven (C.L.F.D.), the Department of Cardiology, Onze Lieve Vrouwe Hospital (B.D.B.), and the Department of Cardiology, Algemeen Stedelijk Hospital Aalst (I.B.), Aalst, the Department of Cardiology, Sint-Jan Hospital, Brugge (J.A.S.V.D.H.), the Department of Cardiology, Hospital Oost-Limburg, Genk (B.F.), and the Department of Cardiology, Imelda Hospital, Bonheiden (J.R.) - all in Belgium; the Department of Cardiology, Institut National de Chirurgie Cardiaque et de Cardiologie Interventionnelle, Luxembourg, Luxembourg (P.F.); and the Department of Cardiology, University Hospital Královské Vinohrady and Third Medical Faculty, Charles University, Prague, Czech Republic (P.T.).

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.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1915152DOI Listing
April 2020

Predicting hospitalisation-associated functional decline in older patients admitted to a cardiac care unit with cardiovascular disease: a prospective cohort study.

BMC Geriatr 2020 03 20;20(1):112. Epub 2020 Mar 20.

Department of Public Health and Primary Care, KU Leuven - University of Leuven, Leuven, Belgium.

Background: Up to one in three of older patients who are hospitalised develop functional decline, which is associated with sustained disability, institutionalisation and death. This study developed and validated a clinical prediction model that identifies patients who are at risk for functional decline during hospitalisation. The predictive value of the model was compared against three models that were developed for patients admitted to a general medical ward.

Methods: A prospective cohort study was performed on two cardiac care units between September 2016 and June 2017. Patients aged 75 years or older were recruited on admission if they were admitted for non-surgical treatment of an acute cardiovascular disease. Hospitalisation-associated functional decline was defined as any decrease on the Katz Index of Activities of Daily Living between hospital admission and discharge. Predictors were selected based on a review of the literature and a prediction score chart was developed based on a multivariate logistic regression model.

Results: A total of 189 patients were recruited and 33% developed functional decline during hospitalisation. A score chart was developed with five predictors that were measured on hospital admission: mobility impairment = 9 points, cognitive impairment = 7 points, loss of appetite = 6 points, depressive symptoms = 5 points, use of physical restraints or having an indwelling urinary catheter = 5 points. The score chart of the developed model demonstrated good calibration and discriminated adequately (C-index = 0.75, 95% CI (0.68-0.83) and better between patients with and without functional decline (chi = 12.8, p = 0.005) than the three previously developed models (range of C-index = 0.65-0.68).

Conclusion: Functional decline is a prevalent complication and can be adequately predicted on hospital admission. A score chart can be used in clinical practice to identify patients who could benefit from preventive interventions. Independent external validation is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12877-020-01510-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082946PMC
March 2020

The Interaction of Platelets with Colorectal Cancer Cells Inhibits Tumor Growth but Promotes Metastasis.

Cancer Res 2020 01 14;80(2):291-303. Epub 2019 Nov 14.

Aix Marseille Univ, INSERM, INRA, Marseille, France.

Platelets promote metastasis, however, their role in tumor growth remains controversial. Here, we investigated the effect of platelet interactions with colorectal tumor cells. Platelets extravasated into the tumor microenvironment and interacted with tumor cells in a cadherin-6-dependent manner. The interaction induced platelet spreading, release of their granule content, and the generation of three types of microparticles (iMP) that expressed platelet markers, tumor markers, or both. The presence of iMPs was confirmed in colorectal cancer tissue specimens. Platelets significantly reduced tumor growth and increased intratumoral macrophages. This was mediated by iMP recruitment of macrophages via the chemoattractants RANTES, MIF, CCL2, and CXCL12 and activation of their tumor cell killing capacity through IFNγ and IL4, which led to cell-cycle arrest of tumor cells in a p21-dependent manner. In contrast, in the bloodstream, iMPs activated endothelial cells and platelets and induced epithelial-to-mesenchymal transition of tumor cells, promoting metastasis. Altogether, these results indicate that depending on the environment, local or bloodstream, the consequences of the interactions between platelets and a tumor may promote or prevent cancer progression. SIGNIFICANCE: Tumor cell interaction with platelets produces chimeric extracellular vesicles that suppress primary tumor growth by activating tumor-eliminating macrophages, while promoting metastasis through EMT and endothelial activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-1181DOI Listing
January 2020

A Thrombin-Activatable Factor X Variant Corrects Hemostasis in a Mouse Model for Hemophilia A.

Thromb Haemost 2019 Dec 22;119(12):1981-1993. Epub 2019 Oct 22.

Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

Engineered recombinant factor X (FX) variants represent a promising strategy to bypass the tenase complex and restore hemostasis in hemophilia patients. Previously, a thrombin-activatable FX variant with fibrinopeptide-A replacing the activation peptide (FX-delAP/FpA) has been described in this regard. Here we show that FX-delAP/FpA is characterized by a sixfold shorter circulatory half-life compared with wild-type FX, limiting its therapeutical applicability. We therefore designed a variant in which the FpA sequence is inserted C-terminal to the FX activation peptide (FX/FpA). FX/FpA displayed a similar survival to wt-FX in clearance experiments and could be converted into FX by thrombin and other activating agents. In in vitro assays, FX/FpA efficiently restored thrombin generation in hemophilia A and hemophilia B plasmas, even in the presence of inhibitory antibodies. Expression following hydrodynamic gene transfer of FX/FpA restored thrombus formation in FVIII-deficient mice in a laser-induced injury model as well as hemostasis in a tail-clip bleeding model. Hemostasis after tail transection in FVIII-deficient mice was also corrected at 5 and 90 minutes after injection of purified FX/FpA. Our data indicate that FX/FpA represents a potential tenase-bypassing agent for the treatment of hemophilia patients with or without inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1697662DOI Listing
December 2019

Clinical Outcomes Following Implantation of Thin-Strut, Bioabsorbable Polymer-Coated, Everolimus-Eluting SYNERGY Stents.

Circ Cardiovasc Interv 2019 09 27;12(9):e008152. Epub 2019 Aug 27.

Boston Scientific Corporation, Marlborough, MA (P.U., D.J.A., I.T.M.).

Background: The thin-strut SYNERGY stent has an abluminal everolimus-eluting bioabsorbable polymer coating designed to facilitate vascular healing and reduce risk of stent thrombosis. In the multicenter, randomized EVOLVE II trial (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]), SYNERGY was noninferior to the durable polymer PROMUS Element Plus everolimus-eluting stent for the primary end point of 1-year target lesion failure. Longer-term clinical follow-up will support the relative efficacy and safety of SYNERGY.

Methods: Patients with ≤3 native coronary lesions (reference vessel diameter ≥2.25-≤4.00 mm; length ≤34 mm) in ≤2 major epicardial vessels were randomized 1:1 to SYNERGY (N=838) or PROMUS Element Plus (N=846). EVOLVE II included a Diabetes substudy which pooled patients with diabetes mellitus from the randomized controlled trial (n=263) and from a sequential, single-arm substudy (N=203).

Results: The 5-year target lesion failure rate was 14.3% for SYNERGY and 14.2% for PROMUS Element Plus (P=0.91). Landmark analysis demonstrated similar rates of target lesion failure from discharge to 1-year (P=0.90) and from 1 to 5 years (P=0.94). Definite/probable stent thrombosis was infrequent in both arms (SYNERGY 0.7% versus PROMUS Element Plus 0.9%; P=0.75). There were no significant differences in the rates of cardiac death, myocardial infarction, or revascularization. Among patients with diabetes mellitus, the target lesion failure rate to 1-year was noninferior to a prespecified performance goal and to 5 years was 17.0%.

Conclusions: SYNERGY demonstrated comparable outcomes to PROMUS Element Plus, with low rates of stent thrombosis and adverse events through 5 years of follow-up. Five-year clinical outcomes were favorable in patients with diabetes mellitus. These data support the long-term safety and effectiveness of SYNERGY in a broad range of patients.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01665053.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008152DOI Listing
September 2019
-->