The clinical significance of peripheral autonomic dysfunction in assessing cardiovascular risk in non-diabetic hypertensive patients is unclear. In a cohort of 93 hypertensive patients without diabetes or neurodegenerative diseases, we examined the correlation between electrochemical skin conductance, arterial stiffness, ambulatory blood pressure parameters, and cardiovascular risk scores. Electrochemical skin conductance was not associated with arterial stiffness or global cardiovascular risk. However, it was lower in older patients and in patients with impaired renal function, suggesting a potential link with microvascular or end-organ involvement.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates in plasma bound to high-density lipoproteins (HDL) and albumin. Circulating S1P levels correlate positively with systolic blood pressure (BP) in hypertension and negatively with severity in septic shock and with left ventricular function in heart disease. In mice, isolated deficiency in HDL-S1P and endothelial cell S1P receptor (R)-1 both trigger hypertension, supporting an essential role for HDL-S1P in endothelial function. Physiological roles of albumin-S1P and myocyte S1PRs in the cardiovascular system remain incompletely defined. We report that mice lacking all circulating S1P pools display hypotension and lack of BP increase with age, which contrasts with HDL-S1P deficiency and suggests an essential role for albumin-S1P in cardiovascular homeostasis. Although cardiac output was preserved in a basal state, left ventricular systolic function and contractile reserve were reduced in the absence of circulating S1P. Cardiac function and BP were partially or fully normalized by transfusion of erythrocytes capable of S1P production. Hypotension was accompanied by reduced peripheral resistance, and albumin-S1P, but not S1P complexed to an HDL-like chaperone, dose-dependently increased vascular resistance in isolated perfused kidneys via S1PR3 and S1PR2. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent BP maintenance and pointed to a distinct origin of the cardiac phenotype. We thus uncover an essential role for circulating S1P in maintaining BP and left ventricular systolic function in mice. Our results also highlight distinct functions for the pools of S1P bound to HDL and to albumin, carrying both diagnostic and therapeutic implications.

G protein-coupled receptors (GPCRs) are key regulators of cardiovascular function that provide targets for the treatment of cardiovascular disease. Sphingosine 1-phosphate (S1P) is an erythrocyte- and platelet-derived lipid mediator with cognate GPCRs on endothelial cells (EC), vascular smooth muscle cells (VSMC) and cardiomyocytes. S1P circulates in plasma bound to apolipoprotein M (ApoM)-containing high-density lipoproteins (HDL) and to albumin. Circulating S1P levels correlate positively with systolic blood pressure in hypertension and negatively with severity in septic shock and with left ventricular (LV) function in coronary heart disease. In mice, impaired S1P binding to HDL or signaling to EC both trigger hypertension, supporting an essential role for HDL-S1P in supporting endothelial function. The roles of albumin-S1P and myocyte S1PRs in cardiovascular homeostasis remain incompletely defined. Contrasting isolated HDL-S1P deficiency, we report that non-selective depletion of circulating S1P pools in mice impairs LV contractile function and induces hypotension and resistance to the spontaneous increase in blood pressure with age. Cardiac output was preserved in naive S1P deficient mice by compensatory LV dilation, but cardiac reserve reduced in a dobutamine stress test. These phenotypes tracked with hematopoietic cell S1P production and were partially or fully reversed by erythrocyte transfusion. Hypotension was accompanied by reduced peripheral resistance, and S1P infusion dose-dependently increased vascular resistance in isolated perfused kidneys from wild-type mice but not mice with compound deficiency in S1PR2&3. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent blood pressure regulation and pointed to a distinct origin of the cardiac phenotype. Although circulating S1P is elevated in hypertensive mice and humans, increasing circulating S1P was not sufficient to induce hypertension in naive mice. These observations suggests that albumin-S1P crosses the endothelium in resistance arteries to gain access to contractile VSMC S1P receptors, and that myocyte S1PR signaling is essential for vascular resistance and blood pressure maintenance in mice. They also highlight the role for plasma chaperones in specifying vascular responses to S1P and the relevance of S1P as a biomarker and potential therapeutic target for blood pressure regulation and heart failure. ### Competing Interest Statement The authors have declared no competing interest.

Introduction La pierre angulaire du traitement de l’artérite à cellules géantes (ACG) repose sur une corticothérapie prolongée autour de 18 mois. Cependant les rechutes d’ACG sont fréquentes, contribuant parfois à allonger la durée de la corticothérapie et les complications de la corticothérapie surviennent chez plus d’un tiers des patients. Ainsi, le tocilizumab (TCZ) au cours de l’ACG à visée d’épargne cortisonique et/ou de prévention des rechutes s’est imposé dans l’arsenal thérapeutique de l’ACG comme incontournable. Cependant, les circonstances d’introduction du TCZ, de même que les modalités d’arrêt du traitement en vie réelle, méritent d’être mieux connus. Notre objectif est de décrire les caractéristiques et profils évolutifs des patients ACG sous TCZ en soins courants au sein d’une cohorte contemporaine. Patients et méthodes La cohorte NEWTON est une cohorte rétrospective multicentrique réalisée à partir de données collectées chez 100 patients ACG diagnostiqués entre 2017 et 2023 selon les critères ACR/EULAR 2022, au sein de laquelle 36 patients ayant reçu un traitement par TCZ dans le cadre de l’ACG ont été analysés et comparés aux 64 patients ACG n’ayant pas reçu de TCZ. Résultats Au sein d’une cohorte multicentrique de 100 patients avec un diagnostic récent d’ACG, 36 % recevaient du TCZ au cours de leur suivi. L’âge médian au diagnostic était de 70,5 [67–78] ans, avec 9 (25 %) hommes. Au diagnostic, les principales manifestations étaient les céphalées temporales inhabituelles chez 30/36 (83 %) et un syndrome inflammatoire chez 30/36 (94,5 %) patients. La biopsie d’artère temporale confirmait le diagnostic chez 26/33 (79 %) patients. Le doppler des artères temporales trouvait un halo chez 7/17 (41 %) patients. Le TEP-scanner au diagnostic trouvait un hypermétabolisme chez 20/27 (74 %) patients. Le TCZ était introduit dans les 4 semaines suivant le diagnostic d’ACG chez 9/36 (25 %), au cours du suivi à visée d’épargne cortisonique chez 7/36 (19 %) et lors d’une rechute chez 20/36 (56 %) patients, dont 11/20 dès la première rechute. Le délai d’introduction du TCZ par rapport à l’initiation de la corticothérapie au diagnostic était de 7 [2–15,25] mois. La durée médiane de suivi était de 40 [24–51] mois. Concernant la tolérance du TCZ au cours du suivi, 4 patients (11 %) ont présenté un épisode de sigmoïdite non compliquée traitée par antibiotiques. En comparant les patients recevant du TCZ (TCZ+, n=36) et ceux ne recevant pas de TCZ (TCZ−, n=64), le sevrage en corticoïdes était plus souvent observé dans le groupe TCZ+ (19/36, 53 %) que dans le groupe TCZ− (26/64, 41 %). Le délai médian de sevrage de la corticothérapie était de 24,5 [18,5–35,5] mois dans le groupe TCZ+ et de 22 [15–29,5] mois dans le groupe TCZ−. On observait 27/36 (75 %) patients rechuteurs dans le groupe TCZ+ alors qu’on observait 23/64 (36 %) de rechuteurs dans le groupe TCZ−. Au cours de l’évolution, 14/36 (39 %) patients interrompaient le traitement par TCZ dont 7/14 (50 %) patients présentaient une rechute après l’arrêt du TCZ. À la fin du suivi, 25/36 (69 %) étaient sous TCZ et 10/36 (28 %) patients étaient sevrés de la corticothérapie dont 7/10 (70 %) patients poursuivaient le TCZ sans prednisone. Conclusion Plus d’un tiers des patients avec un diagnostic récent d’ACG nécessitait un traitement par TCZ au cours de leur suivi, principalement chez des patients ACG rechuteurs. Le TCZ était majoritairement introduit dans l’année suivant le diagnostic d’ACG. Parmi les patients qui interrompaient le TCZ, 50 % rechutaient.

INTRODUCTION:The management of giant cell arteritis (GCA) has evolved with the arrival of tocilizumab (TCZ) and the use of PET/CT. Our objective is to describe the characteristics and followup of patients with recent diagnosis of GCA in current care.PATIENTS AND METHODS:The NEWTON cohort is a monocentric retrospective cohort based on data collected from 60 GCA patients diagnosed between 2017 and 2022 according to the ACR/EULAR 2022 criteria.RESULTS:The median age at diagnosis was 73 [68.75; 81] years old. At diagnosis, the main manifestations were unusual temporal headaches in 48 (80 %) and an inflammatory syndrome in 50 (83 %) patients. Temporal artery biopsy confirmed the diagnosis in 49/58 (84 %) patients. Doppler of the temporal arteries found a halo in 12/23 (52 %) patients. The PET/CT found hypermetabolism in 19/43 (44 %) patients. Prednisone was stopped in 17.5 [12.75; 24.25] months. During follow-up, 22 (37 %) patients received TCZ. At least one complication of corticosteroid therapy was observed in 22 (37 %) patients. After a median follow-up of 24 [12; 42] months, 25 (42 %) patients relapsed. At the end of the follow-up, 29 (48.3 %) patients were weaned from corticosteroid therapy and 15 (25 %) were on TCZ.CONCLUSION:Despite the increasing use of TCZ in the therapeutic arsenal and of the PET/CT in the imaging tools of GCA patients, relapses and complications of corticosteroid therapy remain frequent, observed in more than a third of patients.

Aims Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for the endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet, as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC autonomous S1P production, it is unclear if relative reductions in circulating S1P can cause endothelial dysfunction. It is also unclear how EC S1PR1 insufficiency, whether induced by deficiency in circulating ligand or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets.Methods and results We here fine map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell-type-specific and relative deficiencies in S1P production to define ligand source and dose dependence, and correlate receptor engagement to essential functions. In na & iuml;ve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries, and a subset of high-endothelial venules (HEVs). Similar zonation was observed for albumin extravasation in EC S1PR1-deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic ECs, S1PR1 engagement was high in collecting vessels and lymph nodes and low in blind-ended capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signalling in lymphatics and HEV, haematopoietic cells provided similar to 90% of plasma S1P and sustained signalling in resistance arteries and lung capillaries. S1PR1 signalling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages.Conclusion This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function. Graphical Abstract

Introduction: Cerebral blood flow (CBF) is reduced in patients with Alzheimer's disease (AD). Flow-mediated dilation (FMD), which plays a key role in the regulation of blood flow, is attenuated by endothelin-1. We hypothesized that endothelin receptor blockade may improve CBF in AD.Methods: We investigated cerebrovascular reactivity in a mouse model of AD (APP-PS1; 5-6-month-old male subjects). We assessed the in vivo response to normoxic hypercapnia and in vitro FMD in isolated cerebral and mesenteric resistance arteries before and after endothelin receptor blockade (bosentan).Results: Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 +/- 2.4%; p = 0.006, n = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (-11.4 +/- 1.2%; p < 0.0001, n = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 +/- 2.2%; p < 0.0001, n = 8) but had no effect in WT. FMD was reduced in the posterior cerebral artery of APP-PS1 compared to WT and was normalized by bosentan (1 mu mol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT.Conclusion: APP-PS1 mice exhibited cerebrovascular endothelial dysfunction. Acute and chronic blockade of endothelin receptors restored endothelial vasomotor function, suggesting a promising therapeutic approach to restoring cerebral vasoreactivity in AD.

Background:During the past few decades, several pathophysiological processes contributing to intracranial aneurysm (IA) rupture have been identified, including irregular IA shape, altered hemodynamic stress within the IA, and vessel wall inflammation. The use of preclinical models of IA and imaging tools is paramount to better understand the underlying disease mechanisms.Methods:We used 2 established mouse models of IA, and we analyzed the progression of the IA by magnetic resonance imaging, transcranial Doppler, and histology.Results:In both models of IA, we observed, by transcranial Doppler, a significant decrease of the blood velocities and wall shear stress of the internal carotid arteries. We also observed the formation of tortuous arteries in both models that were correlated with the presence of an aneurysm as confirmed by magnetic resonance imaging and histology. A high grade of tortuosity is associated with a significant decrease of the mean blood flow velocities and a greater artery dilation.Conclusions:Transcranial Doppler is a robust and convenient imaging method to evaluate the progression of IA. Detection of decreased blood flow velocities and increased tortuosity can be used as reliable indicators of IA.

Objectives: Permanent visual impairment is a major complication of giant cell arteritis (GCA). We investigated the added value of color Doppler imaging (CDI) of the central retinal artery (CRA) in patients with suspected GCA for early risk evaluation before temporal artery biopsy (TAB) results become available. Methods: We conducted a non-interventional observational study of 30 consecutive patients hospitalized for suspected GCA, including a comprehensive analysis of clinical, laboratory, imaging, CDI and pathology data. GCA was diagnosed or excluded (GCA+, GCA-, respectively) according to American College of Rheumatology (ACR) criteria and TAB findings. Three patients not meeting ACR criteria were excluded secondarily. The GCAgroup contained ten patients, and the GCA+ group contained 17 patients, including eight with unilateral, transient or permanent clinical visual impairment (CVI). Results: Mean blood flow velocity (mBFV) in the CRA was impaired in the affected eyes of GCA + CVI+ patients (1.9 +/- 0.9 cm.s(-1), p < 0.001) relative to controls (4.1 +/- 1.0 cm.s+213; 1), GCA-patients (3.6 +/- 0.7 cm.s+213; 1) and GCA + CVI- patients (3.8 +/- 0.8 cm.+213; 1). The mBFVs of the CRA was similar for affected and fellow eyes (right or left). CRA mBFV measurements effectively differentiated between patients with and without CVI (ROC-curve analysis, AUC = 0.925 [95%CI: 0.700 to 0.996], p < 0.0001, 88% sensitivity, 89% specificity, and cutoff of <= 2.7 cm.s(-1) for affected eyes; 75% sensitivity, 100% specificity and cutoff of <= 2.2 cm.s+213; 1 for fellow eyes). Conclusion: CDI facilities the early detection of visual ischemia risk in GCA+ patients, justifying urgent high-dose corticosteroid administration to save at least the fellow eye before pathology results become available.

Dysregulated autophagy is associated with cardiovascular and metabolic diseases, where impaired flow-mediated endothelial cell responses promote cardiovascular risk. The mechanism by which the autophagy machinery regulates endothelial functions is complex. We applied multi-omics approaches and in vitro and in vivo functional assays to decipher the diverse roles of autophagy in endothelial cells. We demonstrate that autophagy regulates VEGF-dependent VEGFR signaling and VEGFR-mediated and flow-mediated eNOS activation. Endothelial ATG5 deficiency in vivo results in selective loss of flow-induced vasodilation in mesenteric arteries and kidneys and increased cerebral and renal vascular resistance in vivo. We found a crucial pathophysiological role for autophagy in endothelial cells in flow-mediated outward arterial remodeling, prevention of neointima formation following wire injury, and recovery after myocardial infarction. Together, these findings unravel a fundamental role of autophagy in endothelial function, linking cell proteostasis to mechanosensing.

potential laboratory tools for their prediction, severity, and differential diagnosis.

Au cours de l’artérite à cellules géantes (ACG), l’évaluation de l’activité de l’ACG et les choix thérapeutiques proposés en cas de rechute restent un enjeu important pour le clinicien. Notre objectif est de décrire les caractéristiques des rechutes au sein d’une cohorte de patients avec un diagnostic récent d’ACG porté après 2017. La cohorte NEWTON est une cohorte rétrospective multicentrique réalisée à partir de données collectées chez 100 patients ACG diagnostiqués entre 2017 et 2023 selon les critères ACR/EULAR 1990 et 2022. La rechute était définie comme la réapparition d’un symptôme lié à l’ACG et/ou une élévation de la CRP ≥ 10 mg/L et/ou une apparition ou aggravation d’anomalie à l’imagerie vasculaire nécessitant une majoration de la corticothérapie et/ou l’introduction d’un immunosuppresseur. Au sein d’une cohorte multicentriques de 100 patients avec un diagnostic récent d’ACG, 52/100 (52 %) patients rechutaient. Après un suivi médian de 33 [18 ; 50] mois, 89 rechutes étaient observées chez les 52 patients rechuteurs. On observait 15/52 (29 %) hommes parmi les patients rechuteurs (R+) et 13/48 (27 %) hommes chez les patients non-rechuteurs (R-). Au diagnostic, un hypermétabolisme au PET scanner était observé chez 25/37 (68 %) patients R+ et 25/33 (76 %) patients R-. La rechute était caractérisée par une altération de l’état général dans 62/89 (70 %) rechutes, des céphalées inhabituelles dans 37/89 (42 %) rechutes, des douleurs articulaires dans 21/89 (24 %) rechutes et une atteinte ophtalmologique au cours de 15/89 (17 %) rechutes. Un syndrome inflammatoire biologique était observé dans 43/89 (48 %) des rechutes et une anomalie à l’imagerie au cours de 35/41 (85 %) rechutes. Au cours du suivi, la corticothérapie pouvait être sevrée chez 46/52 (88 %) R+ et chez 47/49 R–. La corticothérapie n’était pas sevrée au moment de la rechute dans 68/89 (76 %) des cas. La dose médiane de prednisone à la rechute était de 8 [4 ; 15] mg par jour. Lors de la rechute, le clinicien augmentait la dose de prednisone en médiane à 20 [10 ; 35] mg par jour, comprenant des bolus de methylprednisolone pour 4 de ces rechutes en raison soit d’une atteinte oculaire, soit une récidive d’AVC. Le TCZ était introduit lors d’une rechute chez 21/52 (40 %) patients. La rechute survenait sous TCZ chez 3 patients. La première rechute survenait dans un délai médian de 258 [113 ; 557] jours, soit 8 [3 ; 17,5] mois. Dans un modèle de cox sur cette cohorte, aucun facteur n’était associé à un risque de rechute de façon significative. Malgré l’utilisation croissante de TCZ dans l’arsenal thérapeutique et du TEP-scanner dans les outils d’imagerie d’évaluation de l’activité de l’ACG, les rechutes concernent encore la moitié des patients et surviennent principalement dès la première année suivant le diagnostic d’ACG. Les 2/3 des rechutes surviennent alors que la corticothérapie n’est pas encore sevrée.

Since the beginning of the pandemic, a high prevalence of VTE has been observed in hospitalized patients with severe COVID-19.1Jiménez D. García-Sanchez A. Rali P. et al.Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis.Chest. 2021; 159: 1182-1196Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar SARS-CoV-2 infection induces major endothelial cell dysfunction with systemic inflammatory response, both resulting in micro- and macrovascular thrombotic events that include pulmonary thrombosis/embolism.1Jiménez D. García-Sanchez A. Rali P. et al.Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis.Chest. 2021; 159: 1182-1196Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar,2Bikdeli B. Madhavan M.V. Jimenez D. et al.COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.J Am Coll Cardiol. 2020; 75: 2950-2973Crossref PubMed Scopus (1691) Google Scholar Although multiple studies have evaluated the efficacy and safety of anticoagulant therapy in patients with COVID-19 with diagnosed VTE during hospital stay, limited data are available regarding outcomes after hospital discharge.3Doyle A.J. Thomas W. Retter A. et al.Updated hospital associated venous thromboembolism outcomes with 90-days follow-up after hospitalisation for severe COVID-19 in two UK critical care units.Thromb Res. 2020; 196: 454-456Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 4Demelo-Rodríguez P. Ordieres-Ortega L. Ji Z. et al.Long-term follow-up of patients with venous thromboembolism and COVID-19: analysis of risk factors for death and major bleeding.Eur J Haematol. 2021; 106: 716-723Crossref PubMed Scopus (10) Google Scholar, 5Fernández-Capitán C. Barba R. Díaz-Pedroche M.D.C. et al.Presenting characteristics, treatment patterns, and outcomes among patients with venous thromboembolism during hospitalization for COVID-19.Semin Thromb Hemost. 2021; 47: 351-361Crossref PubMed Scopus (20) Google Scholar, 6Buso G, Mazzolai L, Rueda-Camino JA, et al. Pulmonary embolism in patients with COVID-19: comparison between different care settings [published online ahead of print December 13, 2021]. Semin Thromb Hemost. https://doi.org/10.1055/s-0041-1740152.Google Scholar, 7Whyte M.B. Barker R. Kelly P.A. et al.Three-month follow-up of pulmonary embolism in patients with COVID-19.Thromb Res. 2021; 201: 113-115Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Notwithstanding the particular pathogenesis of thrombosis in patients with COVID-19, whether SARS-CoV-2 infection is an effective transient VTE risk factor that requires 3 to 6 months of anticoagulant therapy8Moores L.K. Tritschler T. Brosnahan S. et al.Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST Guideline and Expert Panel report.Chest. 2020; 158: 1143-1163Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar is still debated. We aimed to investigate the outcome of patients with COVID-19 with diagnosed VTE during hospital stay while receiving anticoagulant therapy and after its discontinuation over 1-year follow-up evaluation. We conducted a prospective observational cohort study in our university hospital ICU and medical wards. We included all consecutive patients with COVID-19 with VTE diagnosed during hospitalization from March 25, 2020, to April 30, 2021, who were referred after hospital discharge to our outpatient thrombosis unit for follow-up. SARS-CoV-2 infection was diagnosed with the use of standard real-time polymerase chain reaction (Cobas-SARS-CoV-2 kits, Roche, France). COVID-19-related symptomatic VTE, namely pulmonary embolism (PE) and/or DVT, were diagnosed with CT pulmonary angiography and/or duplex ultrasound examination of the lower limb veins by certified ultrasound operators, respectively. Laboratory thrombophilia screening was performed within 24 h of DVT/PE diagnosis (Table 1). VTE prophylaxis and management followed local guidelines in agreement with the international guidelines regarding ICU/non-ICU patients with COVID-19.8Moores L.K. Tritschler T. Brosnahan S. et al.Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST Guideline and Expert Panel report.Chest. 2020; 158: 1143-1163Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar In patients with DVT/PE, we recommended initial anticoagulant therapy with low-molecular-weight heparin (LMWH) or unfractionated heparin if contraindicated, which was changed on discharge to direct oral anticoagulant (DOAC; creatinine clearance ≥ 30 mL/min). For most patients, in the absence of evidence, a 3- to 6-month duration of anticoagulant treatment was proposed, as recommended elsewhere.8Moores L.K. Tritschler T. Brosnahan S. et al.Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST Guideline and Expert Panel report.Chest. 2020; 158: 1143-1163Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar Outcome criteria included symptomatic VTE recurrence (primary outcome) and bleeding event onset (secondary outcome). Visits were planned at 1, 3, 6, and 12 months after VTE diagnosis and beyond if needed. Periodic evaluation included physical examination to assess both outcomes and, when required, duplex ultrasound examination, CT pulmonary angiography, and laboratory reassessment of abnormal thrombophilia parameters if needed away from the acute phase. Bleeding events were adjudicated according to the International Society on Thrombosis and Haemostasis criteria.10Schulman S. Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.J Thromb Hemost. 2005; 3: 692-694Crossref PubMed Scopus (2894) Google Scholar This study was part of the French COVID-19 cohort registry, approved by our institutional ethics committee (IDRCB-2020-A00256-33; CPP-11-20-20.02.04.68737). All participating patients gave their written informed consent. Reporting of the study conforms to broad EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network guidelines. Quantitative variables were expressed as medians (25th to 75th percentiles), and categoric variables were expressed as percentages (version 11.0.1.0; MedCalc Software).Table 1Initial Clinical and Laboratory Characteristics in 48 Patients With COVID-19 and VTE EventsVariableMeasurementPatients characteristics Age, y62 (52-67) Male sex, No. (%)38 (79) BMI, kg/m227.0 (24.3-30.0) Hypertension, No. (%)17 (35) Diabetes mellitus, No. (%)13 (27) History of cardiac disease, No. (%)8 (17) VTE history, No. (%)6 (12)COVID-19-related lung involvementaCOVID-19-related lung involvement (%) refers to parenchymal ground-glass opacities based on CT scan findings as defined by Revel et al.9 < 10%, No. (%)4 (8) 10%-25%, No. (%)15 (31) 25%-50%, No. (%)15 (31) 50%-75%, No. (%)14 (30) Critically ill patients, No. (%)17 (35) Time from first symptoms to VTE diagnosis, d12 (9-16) Time from hospital admission to VTE diagnosis, d0 (0-4)Description of VTE, No. (%) Pulmonary embolism40 (83)Proximal36 (75)Isolated32 (67) Bilateral19 (40) DVT16 (33)Proximal8 (17)Isolated8 (17) (6 in the ICU)Bilateral2 (4)Initial anticoagulant therapy, No. (%) Low molecular weight heparin (therapeutic dose)40 (83) Direct oral anticoagulant6 (13)Apixaban3 (6)Rivaroxaban3 (6) Unfractionated heparin (therapeutic dose)2 (4)Anticoagulant therapy on hospital discharge Direct oral anticoagulant, No. (%)45 (94)Apixaban35 (73)Rivaroxaban10 (21) Low molecular weight heparin (therapeutic dose), No. (%)3 (6) Length of hospital stay, d11 (7-18)Laboratory data Hemoglobin, g/dL12.7 (11.4-13.3) Platelet count, g/L323 (255-386) Leukocytes, g/L8.2 (6.8-10.3) Serum creatinine, μM72.0 (59.0-84.0) Fibrinogen, g/L5.89 (4.8-7.8) D-dimer, ng/mL3,410 (1,990-8,450) Antiphospholipid antibodies,bThrombophilia screening parameters. No. (%)Lupus anticoagulantbThrombophilia screening parameters.,cDiagnosis performed with diluted Russell viper venom time (dRVVT LAC-Screen/LAC-Confirm Siemens), PTT-LA-Stago and Staclot-LA Stago (Diagnostica Stago, Inc, Parsippany-Troy Hills, NJ).,dThe result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation.24 (50)Anti-cardiolipin and/or anti-beta-2-GPI antibodiesbThrombophilia screening parameters.,eQuantified with the use of chemiluminescence assays (Acustar, Werfen).7 (15)Persistence of anti-phospholipid antibodies ≥ 12 wks4 (8) Antithrombin activity,bThrombophilia screening parameters.,dThe result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation.,fNo patient had confirmed natural inhibitor deficiency after anticoagulant cessation. International Units/dL92 (85-102) Protein C clotting activity,bThrombophilia screening parameters.,dThe result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation.,fNo patient had confirmed natural inhibitor deficiency after anticoagulant cessation. International Units/dL82 (66-93) Protein SbThrombophilia screening parameters.,dThe result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation.,fNo patient had confirmed natural inhibitor deficiency after anticoagulant cessation.Clotting activity,bThrombophilia screening parameters.,dThe result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation. International Units/dL58 (41-75)Free antigen,bThrombophilia screening parameters.,dThe result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation. International Units/dL88 (71-111) F2 G20210A variant,bThrombophilia screening parameters. No. (%)4 (8) F5 G1691A variant,bThrombophilia screening parameters. No. (%)2 (4)Results are expressed as median (interquartile range), unless otherwise indicated.a COVID-19-related lung involvement (%) refers to parenchymal ground-glass opacities based on CT scan findings as defined by Revel et al.9Revel M.P. Parkar A.P. Prosch H. et al.COVID-19 patients and the radiology department: advice from the European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI).Eur Radiol. 2020; 30: 4903-4909Crossref PubMed Scopus (206) Google Scholarb Thrombophilia screening parameters.c Diagnosis performed with diluted Russell viper venom time (dRVVT LAC-Screen/LAC-Confirm Siemens), PTT-LA-Stago and Staclot-LA Stago (Diagnostica Stago, Inc, Parsippany-Troy Hills, NJ).d The result could be unreliable in the setting of acute clot and/or anticoagulation: abnormal parameters were reassessed systematically away from the acute phase and after anticoagulant cessation.e Quantified with the use of chemiluminescence assays (Acustar, Werfen).f No patient had confirmed natural inhibitor deficiency after anticoagulant cessation. Open table in a new tab Results are expressed as median (interquartile range), unless otherwise indicated. Over the 13-month study period, of the 59 discharged patients who experienced COVID-19-related VTE during hospital stay, 48 patients (age, 62 years [range, 52 to 67 years]; 38M/10F) were followed in our outpatient thrombosis unit and included in the study (11 patients declined the follow-up). Median follow-up duration was 12 months (range, 12 to 14 months), of which 6 months (range, 5.5 to 6.6 months) were after anticoagulant discontinuation. One patient was lost to follow-up after the first visit. Hospitalization baseline clinical and laboratory characteristics are reported in Table 1. During hospitalization, 40 patients (83%) had PE (eight cases with associated DVT); eight patients (17%) had isolated DVT. Antiphospholipid antibodies that initially were present in 26 patients (54%) persisted in only four patients (8%) after 12 weeks. Forty patients (83%) received LMWH; two patients (4%) received unfractionated heparin, and six patients (13%) received DOAC (apixaban, three patients; rivaroxaban, three patients) for initial VTE management. After discharge, 45 patients (94%) received DOAC (35 apixaban, 35 patients; rivaroxaban, 10 patients) and three patients (6%) received LMWH. Anticoagulants were discontinued after 3 months in one patient with DVT (2%) and after 6 months in 38 additional patients (79%). Anticoagulants were continued in eight patients (16%) in relation to antiphospholipid syndrome (n = 3), VTE history (n = 2), and underlying cancer (n = 3). Outcomes during follow-up are summarized in Figure 1. No symptomatic VTE recurrence was observed during or after anticoagulant therapy discontinuation. One 66-year-old patient with a 6-year history of ischemic cardiomyopathy experienced non-ST-elevation myocardial infarction 5 months after apixaban initiation and underwent coronary stenting with apixaban switch to dual antiplatelet therapy. During the anticoagulant therapy period, five patients (11%) presented bleeding that included three major hemorrhages that affected the GI tract (two patients in-hospital; one patient after discharge) and two minor episodes (both after discharge). One patient with major bleeding further experienced confirmed heparin-induced thrombocytopenia that required heparin to be switched to argatroban, then danaparoïd, and finally to apixaban without bleeding recurrence. In addition, once anticoagulation was stopped, one 66-year-old man with past polycythemia vera (6-month apixaban for PE, then switched to aspirin), died 9 months later from major duodenal hemorrhage (Fig 1). To the best of our knowledge, this is one of the first prospective real-life studies to evaluate outcomes over a 12-month period after COVID-19-related VTE diagnosis in hospitalized patients. We report the absence of VTE recurrence during the follow-up on anticoagulant therapy and after discontinuation. Only few studies reported shorter follow-up periods (from 10 to 159 days) in cohorts of 24 to 737 patients with COVID-19-related VTE,3Doyle A.J. Thomas W. Retter A. et al.Updated hospital associated venous thromboembolism outcomes with 90-days follow-up after hospitalisation for severe COVID-19 in two UK critical care units.Thromb Res. 2020; 196: 454-456Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 4Demelo-Rodríguez P. Ordieres-Ortega L. Ji Z. et al.Long-term follow-up of patients with venous thromboembolism and COVID-19: analysis of risk factors for death and major bleeding.Eur J Haematol. 2021; 106: 716-723Crossref PubMed Scopus (10) Google Scholar, 5Fernández-Capitán C. Barba R. Díaz-Pedroche M.D.C. et al.Presenting characteristics, treatment patterns, and outcomes among patients with venous thromboembolism during hospitalization for COVID-19.Semin Thromb Hemost. 2021; 47: 351-361Crossref PubMed Scopus (20) Google Scholar, 6Buso G, Mazzolai L, Rueda-Camino JA, et al. Pulmonary embolism in patients with COVID-19: comparison between different care settings [published online ahead of print December 13, 2021]. Semin Thromb Hemost. https://doi.org/10.1055/s-0041-1740152.Google Scholar, 7Whyte M.B. Barker R. Kelly P.A. et al.Three-month follow-up of pulmonary embolism in patients with COVID-19.Thromb Res. 2021; 201: 113-115Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar which shows a very low rate of VTE recurrence (0.0% to 2.4%) during anticoagulant therapy, which is consistent with our data. Moreover, we provided new data that confirm the low VTE recurrence risk up to 6 months after anticoagulant discontinuation. This low risk in patients with COVID-19 is similar to what has been observed in patients with VTE that is provoked by a transient nonsurgical factor.11Iorio A. Kearon C. Filippucci E. et al.Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review.Arch Intern Med. 2010; 170: 1710-1716Crossref PubMed Scopus (123) Google Scholar Our data support limited anticoagulant therapy duration of 3 to 6 months in patients with COVID-19, in agreement with current guidelines,8Moores L.K. Tritschler T. Brosnahan S. et al.Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST Guideline and Expert Panel report.Chest. 2020; 158: 1143-1163Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar although selected individuals (eg, with a VTE history) may require long-term anticoagulation. The rate of major bleedings (6.3%) on anticoagulant therapy in our cohort was comparable with those reported in previous studies (2.6% to 11.0%)3Doyle A.J. Thomas W. Retter A. et al.Updated hospital associated venous thromboembolism outcomes with 90-days follow-up after hospitalisation for severe COVID-19 in two UK critical care units.Thromb Res. 2020; 196: 454-456Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 4Demelo-Rodríguez P. Ordieres-Ortega L. Ji Z. et al.Long-term follow-up of patients with venous thromboembolism and COVID-19: analysis of risk factors for death and major bleeding.Eur J Haematol. 2021; 106: 716-723Crossref PubMed Scopus (10) Google Scholar, 5Fernández-Capitán C. Barba R. Díaz-Pedroche M.D.C. et al.Presenting characteristics, treatment patterns, and outcomes among patients with venous thromboembolism during hospitalization for COVID-19.Semin Thromb Hemost. 2021; 47: 351-361Crossref PubMed Scopus (20) Google Scholar, 6Buso G, Mazzolai L, Rueda-Camino JA, et al. Pulmonary embolism in patients with COVID-19: comparison between different care settings [published online ahead of print December 13, 2021]. Semin Thromb Hemost. https://doi.org/10.1055/s-0041-1740152.Google Scholar, 7Whyte M.B. Barker R. Kelly P.A. et al.Three-month follow-up of pulmonary embolism in patients with COVID-19.Thromb Res. 2021; 201: 113-115Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar; however, heterogeneity of patient recruitment and anticoagulant treatment across studies makes comparisons difficult. Despite limitations because of its single-center design and small sample size, our study presents significant strengths such as the inclusion of critically and noncritically ill patients with COVID-19. Moreover, by contrast to other studies, we report outcomes after a relatively long-term anticoagulant therapy discontinuation. To conclude, our study with prospective 1-year follow-up supports the low VTE recurrence risk in either critically or noncritically ill patients with COVID-19 with VTE while receiving anticoagulant therapy and 6 months after its discontinuation. Our data remain to be confirmed in larger cohorts. Financial/nonfinancial disclosures: None declared. Other contributions: The authors thank Clara Noizat, MD, and Charlyne Brakta, PharmD, for helping with data gathering.

OBJECTIVE:COVID-19 is associated with an increased prevalence of deep venous thrombosis (DVT), mainly in the lower limbs. However, the characteristics and rheological conditions, which contribute to facilitating DVT occurrence have been poorly investigated. We aimed to report DVT characteristics, vein diameters and peak blood flow velocities (PBFV) in the common femoral veins (CFVs) of critically ill COVID-19 patients.PATIENTS AND METHODS:We conducted a prospective single-center cohort study in March-October 2020 including all consecutive mechanically ventilated COVID-19 adults. Doppler ultrasound of the lower limbs was performed systematically during the first week of hospitalization. In DVT-free patients, a second Doppler ultrasound was performed seven days later. Data are expressed as medians (interquartile ranges) or percentages. Comparisons were performed using Mann-Whiney and Wilcoxon signed-rank tests or Fischer's exact tests, as appropriate.RESULTS:Fifty-five patients [age, 63 years (56-74); female/male ratio, 0.62; body-mass index, 29 kg/m2 (26-33); hypertension, 47%; diabetes, 38%; ischemic heart disease, 11%] were included. DVT was diagnosed in 19 patients (35%) including in 5 femoral (9%), 2 popliteal (4%) and 12 below-the-knee sites (22%). CFV diameter was increased to 12.0 mm (11.0-15.0) (normal range, 9.1-12) and PBFV reduced to 11.9 cm/s (8.8-15.8) (normal range, 21.3-49.2) [right-side values]. In four patients who had ultrasound before intubation, CFV diameter increased from 12.5 mm (11.8-13.3) before to 14 mm (13.6-15.3) after intubation (p = 0.008).CONCLUSIONS:DVT in the CFV occurred in 9% of the critically ill COVID-19 patients with an overall 35%-DVT prevalence. Venous return difficulty evidenced by larger than normal CFV diameters and lower than normal PBFVs may have facilitated proximal DVT occurrence.

A 64 year old patient presented with wrist pain and fever after radial artery (RA) puncture for coronary angiography. RA ultrasound was normal. One month later, pain and fever persisted; ultrasound imaging (A) and computed tomography angiography (B) revealed an infective radial arteritis with seven staged aneurysms from 6.5 to 10.0 mm in size (asterisks), which required broad spectrum antibiotics (intravenous administration for three days, oral for three weeks). Serial blood cultures did not allow identification of the causal microorganism. Eight months later, the patient was afebrile and the aneurysms had partly regressed while the distal radial artery was occluded without ischaemic symptoms.Image 1

In developed countries, aortic coarctation (AC) is generally diagnosed by fetal echocardiography during the third trimester of pregnancy, or during the neonatal period based on the absence of femoral pulses or the presence of a left supraclavicular systolic murmur. However, AC may be diagnosed late, such as in adult migrants arriving from developing countries without documented medical history although they may require healthcare support during their stay. We report three cases of the incidental diagnosis of thoracic aortic malformations in adults (27, 38 and 43 years) referred for the management of uncontrolled high blood pressure, with major cerebrovascular events for the two oldest. Doppler ultrasound imaging indicated for suspected renal artery stenosis and atheroma lesions revealed abnormal lower-body and normal upper-body arterial blood flow velocity waveforms constitutive of a pathognomonic hemodynamic pattern of AC, a diagnostic which was in all three cases confirmed by multidetector computed tomography-angiography. None of these patients had undergone complete cardiovascular examination, particularly with effective peripheral pulse palpation, during the period preceding the occurrence of major cardiovascular events or at any other time after birth. Our observation suggests that a simple medical examination could have prevented diagnostic wandering and, possibly, the occurrence of severe cerebrovascular complications in two of these three patients.