Publications by authors named "Tristan Mirault"

60 Publications

Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance.

Angiogenesis 2021 May 11. Epub 2021 May 11.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.

Background: Microthrombosis is a hallmark of COVID-19. We previously described von willebrand factor (VWF) and their high molecular weight multimers (HMWMs) as potential trigger of microthrombosis.

Objectives: Investigate VWF activity with collagen-binding assay and ADAMTS13 in COVID-19.

Methods And Results: Our study enrolled 77 hospitalized COVID-19 patients including 37 suffering from a non-critical form and 40 with critical form. Plasma levels of VWF collagen-binding ability (VWF:CB) and ADAMTS13 activity (ADAMTS13:Act) were measured in the first 48 hours following admission. VWF:CB was increased in critical (631% IQR [460-704]) patients compared to non-critical patients (259% [235-330], p < 0.005). VWF:CB was significantly associated (r = 0.564, p < 0.001) with HMWMs. Moreover, median ADAMTS13:Act was lower in critical (64.8 IU/dL IQR 50.0-77.7) than non-critical patients (85.0 IU/dL IQR 75.8-94.7, p < 0.001), even if no patients displayed majors deficits. VWF:Ag-to-ADAMTS13:Act ratio was highly associated with VWF:CB (r = 0.916, p < 0.001). Moreover, VWF:CB level was highly predictive of COVID-19 in-hospital mortality as shown by the ROC curve analysis (AUC = 0.92, p < 0.0001) in which we identified a VWF:CB cut-off of 446% as providing the best predictor sensitivity-specificity balance. We confirmed this cut-off thanks to a Kaplan-Meier estimator analysis (log-rank p < 0.001) and a Cox-proportional Hazard model (HR = 49.1, 95% CI 1.81-1328.2, p = 0.021) adjusted on, BMI, C-reactive protein, and D-dimer levels.

Conclusion: VWF:CB levels could summarize both VWF increased levels and hyper-reactivity subsequent to ADAMTS13 overflow and, therefore, be a valuable and easy to perform clinical biomarker of microthrombosis and COVID-19 severity.
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http://dx.doi.org/10.1007/s10456-021-09789-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111656PMC
May 2021

Renal Outcome and New-Onset Renal and Extrarenal Dissections in Patients With Nontrauma Renal Artery Dissection Associated With Renal Infarction.

Hypertension 2021 May 10:HYPERTENSIONAHA12016540. Epub 2021 May 10.

Hypertension Unit, AP-HP, Hôpital Européen Georges Pompidou, Paris, France. (A.-L.F., G.B., A.L., M.A., L.A.).

We aimed to compare the characteristics of the patients with renal infarction related to nontrauma renal artery dissection (RAD) with versus without an underlying vascular disease and report long-term renal and vascular outcomes, as well as new-onset renal and extra-RADs. Data from 72 consecutive patients with RAD referred to our Hypertension Unit between 2000 and 2015 were analyzed. Radiological data, including a systematic brain-to-pelvis computed tomography angiography, were independently reviewed. Three main causes of RAD were identified at the initial work-up: fibromuscular dysplasia (n=16); dissecting or aneurysmal multisite arterial disease (n=21) not linked to any known vascular disease; and isolated RAD (n=24) without any other arterial lesion. At diagnosis, patients (median age 46 [interquartile range, 40-53] years, 70.5% males, 26.2% preexisting hypertension, 65.6% smokers) had a median blood pressure of 138 (125-152)/87 (78-97) mm Hg. Estimated glomerular filtration rate was 81 (66-95) mL/min per 1.73 m and 18% had renal impairment. Patients were treated with antiplatelet drugs (65.6%), anticoagulant (3.3%). A total of 11.5% underwent angioplasty. No clinical or biological difference was observed between the 3 groups. After 51 (19-92) months follow-up, blood pressure was reduced by 13 (0-29)/9 (3-18) mm Hg; 11.5% of patients had estimated glomerular filtration rate <60 mL/min per 1.73 m. RAD evolved toward healing (67.2%), aneurysmal dilation (24.6%), or stenosis (8.2%). New-onset RAD was as frequent in dissecting or aneurysmal multisite arterial disease (23.8%) than in fibromuscular dysplasia (25%) group, whereas de novo extrarenal dissection was 6-fold more frequent in dissecting or aneurysmal multisite arterial disease (38.1%) than in fibromuscular dysplasia (6.3%) group. No new event occurred in patients with an initial diagnosis of isolated RAD. Initial diagnostic accuracy using thorough systematic exhaustive explorations of arterial sites helps to stratify the risk of new-onset dissection and adapt monitoring accordingly.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16540DOI Listing
May 2021

Lupus anticoagulant single positivity at acute phase is not associated with venous thromboembolism or in-hospital mortality in COVID-19.

Arthritis Rheumatol 2021 Apr 21. Epub 2021 Apr 21.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, F-75006 Paris, France, Respiratory Medicine Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), F-75015, Paris, France.

Introduction: Antiphospholipid antibodies (APA) clinical relevance in COVID-19 is controversial. We aimed to investigate the prevalence and prognostic value of conventional and non-conventional APA in COVID-19 patients.

Methods: This study was a multi-centric, prospective observational French cohort of patients hospitalized for COVID-19 suspicion.

Results: 249 patients were hospitalized for suspected COVID-19, including 154 with confirmed COVID-19 and 95 not confirmed. We found a significant increase in lupus anticoagulant (LA) positivity among COVID-19 positive patients (60.9% versus 23.7% in non-COVID19 patients, p<0.001), while prevalence of conventional (anti-cardiolipin and anti-beta-2-GP1, IgG and IgM isotypes) and non-conventional APA (IgA, anti-phosphatidylserine/prothrombin and anti-prothrombin IgG and IgM) were low in both groups. COVID-19 patients with LA positivity had higher levels of fibrinogen (6.0 IQR 5.0-7.0 versus 5.3 g/L IQR 4.3-6.4, p=0.028) and C-reactive protein (CRP, 115.5 IQR 66.0-204.8 versus 91.8 mg/L IQR 27.0-155.1, p=0.019). Univariate analysis did not show any association between LA positivity and higher risk of venous thromboembolism (VTE, OR 1.02, 95% CI 0.44-2.43, p=0.95) or in-hospital mortality (OR 1.80, 95% CI 0.70-5.05, p=0.24). Unadjusted and adjusted (to CRP, age and sex) Kaplan-Meier survival curves according to LA positivity confirmed the absence of association with VTE or in-hospital mortality (unadjusted: p=0.64 and p=0.26, respectively; adjusted: hazard ratio = 1.13 95% CI 0.48-2.60 and 1.80 95% CI 0.67-5.01).

Conclusions: COVID-19 patients have an increased prevalence of LA positivity associated with biological inflammation markers. However, positive LA at admission is not associated with VTE risk and/or in-hospital mortality.
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http://dx.doi.org/10.1002/art.41777DOI Listing
April 2021

D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort study.

Arch Cardiovasc Dis 2021 Mar 9. Epub 2021 Mar 9.

Université de Paris, PARCC, INSERM, 75015 Paris, France.

Background: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high concentrations of D-dimer, and increased frequency of venous thromboembolism.

Aim: To explore the association between D-dimer at admission and in-hospital mortality in patients hospitalised for COVID-19, with or without symptomatic venous thromboembolism.

Methods: From 26 February to 20 April 2020, D-dimer concentration at admission and outcomes (in-hospital mortality and venous thromboembolism) of patients hospitalised for COVID-19 in medical wards were retrospectively analysed in a multicenter study in 24 French hospitals.

Results: Among 2878 patients enrolled in the study, 1154 (40.1%) patients had D-dimer measurement at admission. Receiver operating characteristic curve analysis identified a D-dimer concentration>1128ng/mL as the best cut-off value for in-hospital mortality (area under the curve 64.9%, 95% confidence interval [CI] 60-69), with a sensitivity of 71.1% (95% CI 62-78) and a specificity of 55.6% (95% CI 52-58), which did not differ in the subgroup of patients with venous thromboembolism during hospitalisation. Among 545 (47.2%) patients with D-dimer concentration>1128ng/mL at admission, 86 (15.8%) deaths occurred during hospitalisation. After adjustment, in Cox proportional hazards and logistic regression models, D-dimer concentration>1128ng/mL at admission was also associated with a worse prognosis, with an odds ratio of 3.07 (95% CI 2.05-4.69; P<0.001) and an adjusted hazard ratio of 2.11 (95% CI 1.31-3.4; P<0.01).

Conclusions: D-dimer concentration>1128ng/mL is a relevant predictive factor for in-hospital mortality in patients hospitalised for COVID-19 in a medical ward, regardless of the occurrence of venous thromboembolism during hospitalisation.
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http://dx.doi.org/10.1016/j.acvd.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942155PMC
March 2021

Placental growth factor level in plasma predicts COVID-19 severity and in-hospital mortality.

J Thromb Haemost 2021 Apr 8. Epub 2021 Apr 8.

Université de Paris, PARCC, INSERM, F-75015, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury.

Objectives: Correlate circulating angiogenic markers VEGF-A, PlGF and FGF-2 to in-hospital mortality in COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF and FGF-2 were measured in each patient ≤48 h following admission.

Results: Study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19 of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF and FGF-2 significantly increase with the severity of the disease (p<0.001). Using a logistic regression model we found a significant association between the increase of FGF-2 or PlGF and mortality (OR 1.11, 95% CI [1.07-1.16], p<0.001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], p<0.001 for PlGF) while no association were found for VEGF-A levels. ROC curve analysis was performed and we identified PlGF above 30 pg/mL as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curves (p=0.001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer and CRP (3.23 95% CI [1.29-8.11], p=0.001).

Conclusion: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19.
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http://dx.doi.org/10.1111/jth.15339DOI Listing
April 2021

Management of carotid stenosis for primary and secondary prevention of stroke: state-of-the-art 2020: a critical review.

Eur Heart J Suppl 2020 Nov 6;22(Suppl M):M35-M42. Epub 2020 Dec 6.

Department of Cardiology, Dupuytren University Hospital, INSERM 1094 & IRD, Limoges, France.

Carotid atherosclerotic plaque is encountered frequently in patients at high cardiovascular risk, especially in the elderly. When plaque reaches 50% of carotid lumen, it induces haemodynamically significant carotid stenosis, for which management is currently at a turning point. Improved control of blood pressure, smoking ban campaigns, and the widespread use of statins have reduced the risk of cerebral infarction to <1% per year. However, about 15% of strokes are still secondary to a carotid stenosis, which can potentially be detected by effective imaging techniques. For symptomatic carotid stenosis, current ESC guidelines put a threshold of 70% for formal indication for revascularization. A revascularization should be discussed for symptomatic stenosis over 50% and for asymptomatic carotid stenosis over 60%. This evaluation should be performed by ultrasound as a first-line examination. As a complement, computed tomography angiography (CTA) and/or magnetic resonance angiography are recommended for evaluating the extent and severity of extracranial carotid stenosis. In perspective, new high-risk markers are currently being developed using markers of plaque neovascularization, plaque inflammation, or plaque tissue stiffness. Medical management of patient with carotid stenosis is always warranted and applied to any patient with atheromatous lesions. Best medical therapy is based on cardiovascular risk factors correction, including lifestyle intervention and a pharmacological treatment. It is based on the tri-therapy strategy with antiplatelet, statins, and ACE inhibitors. The indications for carotid endarterectomy (CEA) and carotid artery stenting (CAS) are similar: for symptomatic patients (recent stroke or transient ischaemic attack ) if stenosis >50%; for asymptomatic patients: tight stenosis (>60%) and a perceived high long-term risk of stroke (determined mainly by imaging criteria). Choice of procedure may be influenced by anatomy (high stenosis, difficult CAS or CEA access, incomplete circle of Willis), prior illness or treatment (radiotherapy, other neck surgery), or patient risk (unable to lie flat, poor AHA assessment). In conclusion, neither systematic nor abandoned, the place of carotid revascularization must necessarily be limited to the plaques at highest risk, leaving a large place for optimized medical treatment as first line management. An evaluation of the value of performing endarterectomy on plaques considered to be at high risk is currently underway in the ACTRIS and CREST 2 studies. These studies, along with the next result of ACST-2 trial, will provide us a more precise strategy in case of carotid stenosis.
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http://dx.doi.org/10.1093/eurheartj/suaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916422PMC
November 2020

Proteinuria and Clinical Outcomes in Hospitalized COVID-19 Patients: A Retrospective Single-Center Study.

Clin J Am Soc Nephrol 2021 Feb 23. Epub 2021 Feb 23.

Université de Paris, Paris, France.

Background And Objectives: Kidney involvement is frequent among patients with coronavirus disease 2019 (COVID-19), and occurrence of AKI is associated with higher mortality in this population. The objective of this study was to describe occurrence and significance of proteinuria in this setting. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS : We conducted a single-center retrospective study to describe the characteristic features of proteinuria measured within 48 hours following admission among patients with COVID-19 admitted in a tertiary care hospital in France, and to evaluate its association with initiation of dialysis, intensive care unit admission, and death.

Results: Among 200 patients with available data, urine protein-creatinine ratio at admission was ≥1 g/g for 84 (42%), although kidney function was normal in most patients, with a median serum creatinine of 0.94 mg/dl (interquartile range, 0.75-1.21). Median urine albumin-creatinine ratio was 110 mg/g (interquartile range, 50-410), with a urine albumin-protein ratio <50% in 92% of patients. Urine retinol binding protein concentrations, available for 85 patients, were ≥0.03 mg/mmol in 62% of patients. Urine protein-creatinine ratio ≥1 g/g was associated with initiation of dialysis (odds ratio, 4.87; 95% confidence interval, 2.03 to 13.0; <0.001), admission to the intensive care unit (odds ratio, 3.55; 95% confidence interval, 1.93 to 6.71; <0.001), and death (odds ratio, 3.56; 95% confidence interval, 1.90 to 6.54; <0.001).

Conclusions: Proteinuria is very frequent among patients admitted for COVID-19 and may precede AKI. Low levels of albuminuria suggest a predominant tubular origin, confirmed by the elevated levels of urine retinol binding protein. Urine protein-creatinine ratio ≥1 g/g at admission is strongly associated with poor kidney and patient outcome.
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http://dx.doi.org/10.2215/CJN.09130620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092053PMC
February 2021

Do Endothelial Colony-forming Cells Come From Bone Marrow or Vessels/VSELs?

Stem Cell Rev Rep 2021 Mar 2. Epub 2021 Mar 2.

Innovative Therapies in Hemostasis, Université de Paris, INSERM, F-75006, Paris, France.

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http://dx.doi.org/10.1007/s12015-021-10140-yDOI Listing
March 2021

Anticoagulation Before Hospitalization Is a Potential Protective Factor for COVID-19: Insight From a French Multicenter Cohort Study.

J Am Heart Assoc 2021 04 8;10(8):e018624. Epub 2021 Feb 8.

PARCC INSERM Université de Paris France.

Background Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with thrombotic outcomes with coagulation and endothelial disorders. Based on that, several anticoagulation guidelines have been proposed. We aimed to determine whether anticoagulation therapy modifies the risk of developing severe COVID-19. Methods and Results Patients with COVID-19 initially admitted in medical wards of 24 French hospitals were included prospectively from February 26 to April 20, 2020. We used a Poisson regression model, Cox proportional hazard model, and matched propensity score to assess the effect of anticoagulation on outcomes (intensive care unit admission or in-hospital mortality). The study enrolled 2878 patients with COVID-19, among whom 382 (13.2%) were treated with oral anticoagulation therapy before hospitalization. After adjustment, anticoagulation therapy before hospitalization was associated with a better prognosis with an adjusted hazard ratio of 0.70 (95% CI, 0.55-0.88). Analyses performed using propensity score matching confirmed that anticoagulation therapy before hospitalization was associated with a better prognosis, with an adjusted hazard ratio of 0.43 (95% CI, 0.29-0.63) for intensive care unit admission and adjusted hazard ratio of 0.76 (95% CI, 0.61-0.98) for composite criteria intensive care unit admission or death. In contrast, therapeutic or prophylactic low- or high-dose anticoagulation started during hospitalization were not associated with any of the outcomes. Conclusions Anticoagulation therapy used before hospitalization in medical wards was associated with a better prognosis in contrast with anticoagulation initiated during hospitalization. Anticoagulation therapy introduced in early disease could better prevent COVID-19-associated coagulopathy and endotheliopathy, and lead to a better prognosis.
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http://dx.doi.org/10.1161/JAHA.120.018624DOI Listing
April 2021

De-aliasing High-Frame-Rate Color Doppler using Dual-wavelength processing.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Feb 3;PP. Epub 2021 Feb 3.

Doppler ultrasound is the premier modality to analyse blood flow dynamics in clinical practice. With conventional systems, Doppler can either provide a time-resolved quantification of the flow dynamics in sample volumes (Spectral Doppler) or an average Doppler velocity/power (Color Flow Imaging) in a wide field of view but with a limited frame rate. The recent development of ultrafast parallel systems made it possible to evaluate simultaneously Color, Power and Spectral Doppler in a wide field of view and at high - frame rates but at the expense of SNR. However, like conventional Doppler, Ultrafast Doppler is subject to aliasing for large velocities and/or large depths. In a recent study, staggered multi-PRF sequences were investigated to de-alias color-Doppler images. In this work, we exploit the broadband nature of pulse-echo ultrasound and propose a dual-wavelength approach for CFI de-aliasing with a constant PRF. We tested the dual-wavelength band-pass processing, in silico in laminar flow phantom and validated it in-vivo in human carotid arteries (n=25). The in silico results showed that the Nyquist velocity could be extended up to 4 times the theoretical limit. In-vivo, de-aliased CFI were highly consistent with unfolded Spectral Doppler (r2 = 0.83, y = 1.1 x + 0.1, N = 25) and provided consistent vector flow images. Our results demonstrate that dual-wavelength processing is an efficient method for high-velocity CFI.
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http://dx.doi.org/10.1109/TUFFC.2021.3056932DOI Listing
February 2021

Role of oculocerebrorenal syndrome of Lowe (OCRL) protein in megakaryocyte maturation, platelet production and functions: a study in patients with Lowe syndrome.

Br J Haematol 2021 Mar 2;192(5):909-921. Epub 2021 Feb 2.

Université de Paris, Innovations Thérapeutiques en Hémostase, Paris, INSERM U1140, France.

Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1) genetic disorder resulting in a defect of the OCRL protein, a phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various domains including a Rho GTPase-activating protein (RhoGAP) homology domain catalytically inactive. We previously reported surgery-associated bleeding in patients with LS, suggestive of platelet dysfunction, accompanied with a mild thrombocytopenia in several patients. To decipher the role of OCRL in platelet functions and in megakaryocyte (MK) maturation, we conducted a case-control study on 15 patients with LS (NCT01314560). While all had a drastically reduced expression of OCRL, this deficiency did not affect platelet aggregability, but resulted in delayed thrombus formation on collagen under flow conditions, defective platelet spreading on fibrinogen and impaired clot retraction. We evidenced alterations of the myosin light chain phosphorylation (P-MLC), with defective Rac1 activity and, inversely, elevated active RhoA. Altered cytoskeleton dynamics was also observed in cultured patient MKs showing deficient proplatelet extension with increased P-MLC that was confirmed using control MKs transfected with OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also had an increased proportion of circulating barbell-shaped proplatelets. Our present study establishes that a deficiency of the OCRL protein results in a defective actomyosin cytoskeleton reorganisation in both MKs and platelets, altering both thrombopoiesis and some platelet responses to activation necessary to ensure haemostasis.
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http://dx.doi.org/10.1111/bjh.17346DOI Listing
March 2021

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.

Angiogenesis 2021 Jan 15. Epub 2021 Jan 15.

Université de Paris, Institut Cochin, INSERM, 75014 Paris, France, Hematology Department Assistance Publique Hôpitaux de Paris. Centre-Université de Paris (APHP-CUP), Cochin Hospital, 75014, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis.

Objectives: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.

Results: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels.

Conclusion: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.
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http://dx.doi.org/10.1007/s10456-020-09762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809553PMC
January 2021

Impact of integrating objective structured clinical examination into academic student assessment: Large-scale experience in a French medical school.

PLoS One 2021 14;16(1):e0245439. Epub 2021 Jan 14.

Université de Paris, Faculté de Médecine, Paris, France.

Purpose: Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities.

Methods: Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1-3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking.

Results: The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P<0.001) or traineeship skill grades (r = 0.17, P = 0.001), respectively, and not with traineeship behavior grades (P>0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking.

Conclusion: This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808634PMC
January 2021

Acute Digital Ischemia After Arterial Injection of Crushed Zolpidem Tablets: Role of Microcrystalline Cellulose? A Case Report.

Front Pharmacol 2020 3;11:560382. Epub 2020 Dec 3.

Vascular Medicine, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, APHP centre Université de Paris, Paris, France.

Literature is scarce on acute ischemia after intra-arterial injection of crushed tablets and no effective medical treatment against the progression of lesions is reported. The only factor able to modify the outcome is the delay between injection and management by a specialized vascular team. Moreover the risk of necrosis seems higher after benzodiazepine intra-arterial injection than with other drugs. We tried to find out mechanistic explanations. We report on the case of a 31-year-old drug addict woman who self-injected into her left brachial artery crushed tablets of zolpidem. She developed an acute ischemia of the left hand, with necrosis of the intermediate and distal phalanges of fingers II, III, and IV. Angiogram of the left upper arm confirmed the distal arterial occlusions with no run-off after the palmar arch in the necrotic fingers. Once she was admitted into our vascular unit, intravenous vasodilator therapy by iloprost, heparin and local protective care were rapidly introduced. After delineation between living and necrotic tissues, she required distal amputations of the affected fingers. The clinical severity of arterial injections of benzodiazepine tablets is linked to the association of several pathophysiological mechanisms. Rather than related benzodiazepine pharmacologic effects with tissue ischemia, by the inhibition of phosphodiesterase, a vasodilator intermediate, or through the peripheral benzodiazepine-type receptor, the predominant mechanism is more likely in relation with microcrystalline cellulose, one component of zolpidem tablets, known as potential embolic agents. They are insoluble and resistant to degradation in water. These properties are probably prominent in the case we described here. Through this case report we want to drag attention of physicians in charge of a patient with acute ischemia after crushed tablet accidental intra-arterial injection, not only to look at the drug injected but also the other components of the tablet and especially to microcrystalline cellulose.
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http://dx.doi.org/10.3389/fphar.2020.560382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775664PMC
December 2020

Predictive Factor for COVID-19 Worsening: Insights for High-Sensitivity Troponin and D-Dimer and Correlation With Right Ventricular Afterload.

Front Med (Lausanne) 2020 12;7:586307. Epub 2020 Nov 12.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France.

Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU). Analyzing the clinical and biological profiles of COVID-19 patients at admission. Among 99 consecutive patients that fulfilled criteria for hospitalization, 48 were hospitalized in the medicine department, 21 were first admitted to the medicine ward department and referred later to ICU, and 30 were directly admitted to ICU from the emergency department. At admission, patients requiring ICU were more likely to have lymphopenia, decreased SpO, a D-dimer level above 1,000 ng/mL, and a higher high-sensitivity cardiac troponin (Hs-cTnI) level. A receiver operating characteristic curve analysis identified Hs-cTnI above 9.75 pg/mL as the best predictive criteria for ICU referral [area under the curve (AUC), 86.4; 95% CI, 76.6-96.2]. This cutoff for Hs-cTnI was confirmed in univariate [odds ratio (OR), 22.8; 95% CI, 6.0-116.2] and multivariate analysis after adjustment for D-dimer level (adjusted OR, 20.85; 95% CI, 4.76-128.4). Transthoracic echocardiography parameters subsequently measured in 72 patients showed an increased right ventricular (RV) afterload correlated with Hs-cTnI ( = 0.42, = 0.010) and D-dimer ( = 0.18, = 0.047). Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with RV dilatation probably reflects a myocardial injury due to an increased RV wall tension. This reinforces the hypothesis of a COVID-19-associated microvascular thrombosis inducing a higher RV afterload.
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http://dx.doi.org/10.3389/fmed.2020.586307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689153PMC
November 2020

Multidimensional Proteomic Approach of Endothelial Progenitors Demonstrate Expression of KDR Restricted to CD19 Cells.

Stem Cell Rev Rep 2021 04 17;17(2):639-651. Epub 2020 Nov 17.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, F-75006, Paris, France.

Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. However, the phenotype of circulating EPCs remains elusive but they are more often described as CD34KDR. The aim of the study was to extensively characterize circulating potential vasculogenic stem cell candidates in two populations of patients with cardiovascular disease by powerful multidimensional single cell complementary cytometric approaches (mass, imaging and flow). We identified cellular candidates in one patient before and after bioprosthetic total artificial heart implantation and results were confirmed in healthy peripheral and cord blood by mass cytometry. We also quantified cellular candidates in 10 patients with different COVID-19 severity. Both C-TAH implantation and COVID-19 at critical stage induce a redistribution of circulating CD34 and CD19 sub-populations in peripheral blood. After C-TAH implantation, circulating CD34 progenitor cells expressed c-Kit stem marker while specific subsets CD34CD133CD45c-KitKDR were mobilized. KDR was only expressed by CD19 B-lymphocytes and CD14 monocytes subpopulations in circulation. We confirmed by mass cytometry this KDR expression on CD19 in healthy peripheral and cord blood, also with a VE-cadherin expression, confirming absence of endothelial lineage marker on CD34 subtypes. In COVID-19, a significant mobilization of CD34c-KitKDR cells was observed between moderate and critical COVID-19 patients regardless CD133 or CD45 expression. In order to better evaluate EPC phenotype, we performed imaging flow cytometry measurements of immature CD34KDR cells in cord blood and showed that, after elimination of non-circular events, those cells were all CD19. During COVID-19, a significant mobilization of CD19KDR per million of CD45 cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34c-Kit cells are mobilized in both cardiovascular disease described here. KDR cells in peripheral blood are CD19 positive cells and are not classic vasculogenic stem and/or progenitor cells. A better evaluation of c-Kit and KDR expressing cells will lead to the redefinition of circulating endothelial progenitors.Graphical abstract Central illustration figure. Multidimensional proteomic approach of endothelial progenitors demonstrate expression of KDR restricted to CD19 cells. Endothelial progenitor cells (EPCs) are involved in cardiovascular diseases, however their phenotype remains elusive. We elucidated here EPCs phenotype by a deep characterization by multidimensional single cell complementary cytometric approaches after Bioprosthetic total artificial heart implantation and during COVID-19. We showed a redistribution of circulating CD34 and CD19 sub-populations in both situations. None of the immature cell population expresses KDR. Mobilized CD34 expressed c-Kit. Imaging flow cytometry demonstrated that CD34KDR cells, after elimination of non-circular events, are all CD19. Our results suggest a new definition of circulating EPCs and emphasize involvement of CD19 cells in cardiovascular disease.
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http://dx.doi.org/10.1007/s12015-020-10062-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670993PMC
April 2021

Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.

Thromb Res 2021 01 7;197:94-99. Epub 2020 Nov 7.

Université de Paris, France; Groupe Hospitalier Paris Saint-Joseph, F-75014 Paris, France; Department of Vascular Medicine, France; INSERM CRESS UMR 1153, F-75005 Paris, France.

Introduction: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Previous studies reported pulmonary embolism (PE) in severe COVID-19 patients. Aim of the study was to estimate the prevalence of symptomatic PE in COVID-19 patients and to identify the clinical, radiological or biological characteristics associated with PE.

Patients/methods: We conducted a retrospective nested case-control study in 2 French hospitals. Controls were matched in a 1:2 ratio on the basis of age, sex and center. PE patients with COVID-19 were compared to patients in whom PE was ruled out (CTPA controls) and in whom PE has not been investigated (CT controls).

Results: PE was suspected in 269 patients among 1042 COVID-19 patients, and confirmed in 59 patients (5.6%). Half of PE was diagnosed at COVID-19 diagnosis. PE patients did not differ from CT and CTPA controls for thrombosis risk factors. PE patients more often required invasive ventilation compared to CTPA controls (odds ratio (OR) 2.79; 95% confidence interval (CI) 1.33-5.84) and to CT controls (OR 8.07; 95% CI 2.70-23.82). PE patients exhibited more extensive parenchymal lesions (>50%) than CT controls (OR 3.90; 95% CI 1.54-9.94). D-dimer levels were 5.1 (95% CI 1.90-13.76) times higher in PE patients than CTPA controls.

Conclusions: Our results suggest a PE prevalence in COVID-19 patients close to 5% in the whole population and to 20% of the clinically suspected population. PE seems to be associated with more extensive lung damage and to require more frequently invasive ventilation.
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http://dx.doi.org/10.1016/j.thromres.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648521PMC
January 2021

Aortic Dissection in an Undiagnosed Familial Form of Bicuspid Aortic Valve with a Short Raphe.

CASE (Phila) 2020 Oct 20;4(5):443-447. Epub 2020 Aug 20.

Vascular Medicine Department, Georges Pompidou European Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1016/j.case.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581640PMC
October 2020

Unexpected diagnosis of COVID-19-associated disorders by SARS-CoV-2-specific serology.

J Clin Virol 2020 11 4;132:104568. Epub 2020 Aug 4.

Laboratoire de Virologie, Service de Microbiologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Unité de Génomique Fonctionnelle des Tumeurs Solides, Centre de Recherche des Cordeliers, INSERM, Université Paris, Paris, France. Electronic address:

Facing the ongoing pandemic caused by SARS-CoV-2, there is an urgent need for serological assays identifying individuals with on-going infection as well as past coronavirus infectious disease 2019 (COVID-19). We herein evaluated the analytical performances of the CE IVD-labeled Abbott SARS-CoV-2 IgG assay (Des Plaines, IL, USA) carried out with the automated Abbott Architect™ i2000 platform at Hôpital Européen Georges Pompidou, Paris, France, using serum sample panels obtained from health-workers with COVID-19 history confirmed by positive nucleic acid amplification-based diagnosis and from patients randomly selected for whom serum samples were collected before the COVID-19 epidemic. The Abbott SARS-CoV-2 IgG assay showed sensitivity of 94 % and specificity of 100 %, demonstrating high analytical performances allowing convenient management of suspected on-going and past-infections. In addition, the SARS-CoV-2 IgG positivity rates were compared in COVID-19 positive and COVID-19 free areas from our hospital. Thus, the frequency of SARS-CoV-2-specific IgG was around 10-fold higher in COVID-19 areas than COVID-19 free areas (75 % versus 8%; P < 0.001). Interestingly, several inpatients hospitalized in COVID-19 free areas suffering from a wide range of unexplained clinical features including cardiac, vascular, renal, metabolic and infectious disorders, were unexpectedly found seropositive for SARS-CoV-2 IgG by systematic routine serology, suggesting possible causal involvement of SARS-CoV-2 infection. Taken together, these observations highlight the potential interest of SARS-CoV-2-specific serology in the context of COVID-19 epidemic, especially to assess past SARS-CoV-2 infection as well as possible unexpected COVID-19-associated disorders.
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http://dx.doi.org/10.1016/j.jcv.2020.104568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402112PMC
November 2020

Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration.

J Thromb Haemost 2020 11 1;18(11):2958-2967. Epub 2020 Oct 1.

Feinstein Institutes for Medical Research and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY, USA.

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed.

Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate.

Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials.

Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.
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http://dx.doi.org/10.1111/jth.15094DOI Listing
November 2020

Non-invasive recanalization of deep venous thrombosis by high frequency ultrasound in a swine model with follow-up.

J Thromb Haemost 2020 11 6;18(11):2889-2898. Epub 2020 Sep 6.

Physics for Medicine Paris, INSERM U1273, ESPCI Paris, CNRS FRE 2031, PSL Research University, Paris, France.

Aims: Pulsed cavitational ultrasound therapy (thombotripsy) allows the accurate fractionation of a distant thrombus. We aimed to evaluate the efficacy and safety of non-invasive thrombotripsy using a robotic assisted and high frequency ultrasound approach to recanalize proximal deep venous thrombosis (DVT) in a swine model.

Methods: Occlusive thrombosis was obtained with a dual jugular and femoral endoveinous approach. The therapeutic device was composed of a 2.25 MHz focused transducer centered by a linear ultrasound probe, and a robotic arm. The feasibility, security, and efficacy (venous channel patency) assessment after thrombotripsy was performed on 13 pigs with acute occluded DVT. To assess the mid-term efficacy of this technique, 8 pigs were followed up for 14 days after thrombotripsy and compared with 8 control pigs. The primary efficacy endpoint was the venous patency. Safety was assessed by the search for local vessel wall injury and pulmonary embolism.

Results: We succeeded in treating all pigs except two with no accessible femoral vein. After median treatment duration of 23 minutes of cavitation, all treated DVT were fully recanalized acutely. At 14 days, in the treated group, six of the eight pigs had a persistent patent vein and two pigs had a venous reocclusion. In the control group all pigs had a persistent venous occlusion. At sacrifice, no local vein nor arterial wall damage were observed as well as no evidence of pulmonary embolism in all pigs.

Conclusion: High frequency thrombotripsy seems to be effective and safe for non-invasive venous recanalization of DVT.
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http://dx.doi.org/10.1111/jth.15034DOI Listing
November 2020

Curative anticoagulation prevents endothelial lesion in COVID-19 patients.

J Thromb Haemost 2020 09 30;18(9):2391-2399. Epub 2020 Jul 30.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France.

Background: Coronavirus disease-2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders.

Objectives: To explore the coagulopathy and endothelial dysfunction in COVID-19 patients.

Methods: The study analyzed clinical and biological profiles of patients with suspected COVID-19 infection at admission, including hemostasis tests and quantification of circulating endothelial cells (CECs).

Results: Among 96 consecutive COVID-19-suspected patients fulfilling criteria for hospitalization, 66 were tested positive for SARS-CoV-2. COVID-19-positive patients were more likely to present with fever (P = .02), cough (P = .03), and pneumonia at computed tomography (CT) scan (P = .002) at admission. Prevalence of D-dimer >500 ng/mL was higher in COVID-19-positive patients (74.2% versus 43.3%; P = .007). No sign of disseminated intravascular coagulation were identified. Adding D-dimers >500 ng/mL to gender and pneumonia at CT scan in receiver operating characteristic curve analysis significantly increased area under the curve for COVID-19 diagnosis. COVID-19-positive patients had significantly more CECs at admission (P = .008) than COVID-19-negative ones. COVID-19-positive patients treated with curative anticoagulant prior to admission had fewer CECs (P = .02) than those without. Interestingly, patients treated with curative anticoagulation and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers had even fewer CECs (P = .007).

Conclusion: Curative anticoagulation could prevent COVID-19-associated coagulopathy and endothelial lesion.
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http://dx.doi.org/10.1111/jth.14968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323356PMC
September 2020

Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients.

Angiogenesis 2020 11 27;23(4):611-620. Epub 2020 May 27.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.

Background: Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis.

Objectives: To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening.

Methods: Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission.

Results: Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers.

Conclusion: Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.
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http://dx.doi.org/10.1007/s10456-020-09730-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250589PMC
November 2020

Innovative Multiparametric Characterization of Carotid Plaque Vulnerability by Ultrasound.

Front Physiol 2020 3;11:157. Epub 2020 Mar 3.

Physics for Medicine Paris, INSERM U1273, ESPCI Paris, CNRS FRE 2031, PSL Research University, Paris, France.

Objective: The degree of stenosis of a carotid plaque is a well-established risk factor for ischemic stroke. Nevertheless, the risk of ipsilateral stroke in asymptomatic carotid stenosis remains low and new imaging markers are needed to better target which patients would benefit most from endarterectomy or intensive medical therapy. Ultrafast ultrasound imaging offers parameters helping at characterizing the carotid plaque by shear wave elastography and Ultrafast Doppler (UFD). We aimed at using these techniques to characterize 3 different ultrasound biomarkers: plaque stiffness heterogeneity, wall shear stress (WSS) and intraplaque micro-flows and to correlate these biomarkers with findings on computed tomography angiography (CTA) and the pathological examination.

Methods: We present the case of a multimodal evaluation of a carotid plaque using ultrasound. Elastography has been coupled to the WSS assessment and the detection of intraplaque micro-flows by UFD. The data have been compared to CTA and to the pathology examination of the tissue after carotid endarterectomy.

Results: Elastography allowed at identifying stiff areas corresponding to calcifications, as well as a soft area corresponding to an intraplaque hemorrhage. The flow evaluation with UFD showed an increase of the WSS along the plaque and identified the presence of a plaque rupture, confirmed by the pathologist.

Conclusion: Ultrafast ultrasound imaging is an innovative, easily accessible technique that provides imaging modalities on top of the conventional B-mode. Ultrafast ultrasound biomarkers such as plaque stiffness heterogeneity, WSS and intraplaque micro-flows could help to define the vulnerability of the carotid plaque in order to stratify patients that could benefit most from endarterectomy or intensive medical therapy.
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http://dx.doi.org/10.3389/fphys.2020.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064056PMC
March 2020

Prognosis of large vessel involvement in large vessel vasculitis.

J Autoimmun 2020 03 5;108:102419. Epub 2020 Feb 5.

Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto- Inflammatoires, F-75013, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, And Inflammation- Immunopathology-Biotherapy Department (DHU I2B), F-75005, Paris, France; INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, France. Electronic address:

Objectives: To assess prognosis factors and outcome of large vessel involvement (LVI) in large vessels vasculitis (LVV) patients.

Methods: Retrospective multicenter study of characteristics and outcomes of 417 patients with LVI including 299 Takayasu arteritis (TAK) and 118 Giant cell arteritis (GCA-LVI) were analyzed. Logistic regression analysis assessed prognosis factors in LVV patients. Outcome of LVI among TAK and GCA-LVI patients (ischemic complications, aneurysms complications, relapses and revascularization) were assessed.

Results: In multivariable analysis, stroke/transient ischemic attack [HR: 3.63 (1.46-9.04), p = 0.006] was independently associated with vascular complications in LVV. The 10-years aneurysm free survival was significantly lower [67% (48-93) vs 89% (84-95), p = 0.02] in GCA-LVI compare to TAK patients. The 5-years relapse free survival was significantly lower [47% (37-60) vs 69% (63-75), p < 0.001,] in GCA-LVI compare to TAK patients. The 10-years revascularization free survival was significantly lower [55% (48-64) vs 76% (59-99), p < 0.001] in TAK compare to GCA-LVI patients. After a median follow-up of 5 years, 16 (5.4%) TAK and 7 (5.9%) GCA-LVI patients died, mainly of aneurysm (26%) and ischemic complications (26%).

Conclusion: This large nationwide cohort of LVI provided prognosis factors of vascular complications in LVV patients. TAK and GCA-LVI have different long-term outcome in term of aneurysm development, relapse and revascularization.
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http://dx.doi.org/10.1016/j.jaut.2020.102419DOI Listing
March 2020

Wall Shear Stress Measurement by Ultrafast Vector Flow Imaging for Atherosclerotic Carotid Stenosis.

Ultraschall Med 2019 Dec 19. Epub 2019 Dec 19.

INSERM U1273, Physics for Medicine, ESPCI Paris, CNRS FRE 2031, PSL Research University, Paris, France.

Objective:  Carotid plaque vulnerability assessment could guide the decision to perform endarterectomy. Ultrafast ultrasound imaging (UF) can evaluate local flow velocities over an entire 2D image, allowing measurement of the wall shear stress (WSS). We aimed at evaluating the feasibility of WSS measurement in a prospective series of patients with carotid stenosis.

Methods:  UF acquisitions, performed with a linear probe, had an effective frame rate of 5000 Hz. The flow velocity was imaged over the entire plaque area. WSS was computed with the vector field speed using the formula: with the blood velocity and μ, the blood viscosity. The WSS measurement method was validated using a calibrated phantom. In vivo, WSS was analyzed in 5 areas of the carotid wall: common carotid artery, plaque ascent, plaque peak, plaque descent, internal carotid artery.

Results:  Good correlation was found between in vitro measurement and the theoretical WSS values (R = 0.95; p < 0.001). 33 patients were prospectively evaluated, with a median carotid stenosis degree of 80 % [75-85]. The maximum WSS value over the cardiac cycle follows the shape of the plaque with an increase during the ascent, reaching its maximum value of 3.25 Pa [2.26-4.38] at the peak of the plaque, and a decrease after passing of the peak (0.93 Pa [0.80-1.19]) lower than the WSS values in the non-stenotic areas (1.47 Pa [1.12-1.77] for the common carotid artery).

Conclusion:  UF allowed local and direct evaluation of the plaque's WSS, thus better characterizing local hemodynamics to identify areas of vulnerability.

Key Points:   · Ultrafast vector Doppler allows calculation of the wall shear stress (WSS) by measuring velocity vectors over the entire 2D image.. · The setup to measure the WSS has been validated in vitro on a linear flow phantom by comparing measurements to in silico calculations.. · Applying this method to carotid plaque allows us to better describe the hemodynamic constraints that apply along the entire length of the plaque..
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http://dx.doi.org/10.1055/a-1060-0529DOI Listing
December 2019

Carotid Stiffness Assessment With Ultrafast Ultrasound Imaging in Case of Bicuspid Aortic Valve.

Front Physiol 2019 23;10:1330. Epub 2019 Oct 23.

VASC European Research Network, Centre de Référence des Maladies Vasculaires Rares, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.

Aims: To compare the carotid stiffness and flow parameters by ultrafast ultrasound imaging (UF), in bicuspid aortic valve (BAV) patients to first-degree relatives (controls).

Methods: BAV patients ( = 92) and controls ( = 48) were consecutively included at a reference center for BAV. Aortic valve and ascending aorta were evaluated by echocardiography. Common carotid arteries were evaluated by UF with a linear probe. A high frame rate (2,000 frames/s) was used to measure the pulse wave velocity (PWV). The arterial diameter change over the cardiac cycle was obtained by UF-Doppler imaging. This allowed us to measure the distensibility and the maximal rate of systolic distension (MRSD). The wall shear stress (WSS) was measured based on the same acquisitions, by analyzing blood flow velocities close to the carotid walls.

Results: BAV patients had significantly larger aortic diameters ( < 0.001) at the Valsalva sinus and at the tubular ascending aorta but no larger carotid diameters. No significant differences were found in carotid stiffness parameters (distensibility, MRSD, and PWV), even though these patients had a higher aortic stiffness. Carotid stiffness correlated linearly with age and similar slopes were obtained for BAV patients and controls. No difference in carotid WSS was found between BAV patients and controls.

Conclusion: Our results clearly show that the carotid stiffness and flow parameters are not altered in case of BAV compared with controls.
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http://dx.doi.org/10.3389/fphys.2019.01330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819321PMC
October 2019

Aortic Wall Elastic Properties in Case of Bicuspid Aortic Valve.

Front Physiol 2019 10;10:299. Epub 2019 Apr 10.

Centre de Référence des Maladies Vasculaires Rares, Hôpital Européen Georges-Pompidou, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.

Purpose Of The Review: Bicuspid aortic valve (BAV) is associated with a significant risk of development of aneurysm and dissection of the ascending thoracic aorta. Development of what is called BAV associated aortopathy is particularly heterogeneous with an uncertain prognosis and with no prognostic biomarkers except for the aortic diameter. This situation leads to an important variability of the therapeutic strategy of this aortopathy. By reviewing the literature on aortic stiffness in the case of BAV, we aimed at evaluating its potential prognostic role in the development of aortic dilatation.

Recent Findings: Studies evaluating aortic stiffness, with ultrasound or magnetic resonance imaging, converge toward the description of an increased segmental aortic stiffness in BAV patients regardless of age, diameter or aortic level, from the root to the arch. Even though there is a lack of longitudinal studies evaluating the progression of aortic dilatation, new data have recently shown the potential prognostic role of the maximal rate of systolic distension of the aortic wall with magnetic resonance imaging.

Summary: Although the use of aortic distensibility calculation is a simple evaluation of stiffness that could be easily transposed in daily practice, its interpretation remains uncertain. New arterial stiffening indicators seem more promising but need a stronger validation.
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http://dx.doi.org/10.3389/fphys.2019.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467952PMC
April 2019

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

J Am Coll Cardiol 2019 04;73(15):1948-1957

AP-HP, Hôpital Européen Georges Pompidou, Département de Génétique, Centre de Référence des Maladies Vasculaires Rares, Paris, France; INSERM, U 970, Paris Centre de Recherche Cardiovasculaire-PARCC, Paris, France; Université Paris Sorbonne Cité, Faculté de Médecine Paris Descartes, Paris, France. Electronic address:

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality.

Objectives: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center.

Methods: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient.

Results: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011.

Conclusions: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.
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http://dx.doi.org/10.1016/j.jacc.2019.01.058DOI Listing
April 2019