Cécile Oury

Sepsis prediction in critically ill patients by platelet activation markers on ICU admission: a prospective pilot study

BackgroundPlatelets have been involved in both immune surveillance and host defense against severe infection. To date, whether platelet phenotype or other hemostasis components could be associated with predisposition to sepsis in critical illness remains unknown. The aim of this work was to identify platelet markers that could predict sepsis occurrence in critically ill injured patients.MethodsThis single-center, prospective, observational, 7-month study was based on a cohort of 99 non-infected adult patients admitted to ICUs for elective cardiac surgery, trauma, acute brain injury, and post-operative prolonged ventilation and followed up during ICU stay. Clinical characteristics and severity score (SOFA) were recorded on admission. Platelet activation markers, including fibrinogen binding to platelets, platelet membrane P-selectin expression, plasma soluble CD40L, and platelet-leukocytes aggregates were assayed by flow cytometry at admission and 48xa0h later, and then at the time of sepsis diagnosis (Sepsis-3 criteria) and 7xa0days later for sepsis patients. Hospitalization data and outcomes were also recorded.MethodsOf the 99 patients, 19 developed sepsis after a median time of 5xa0days. These patients had a higher SOFA score at admission; levels of fibrinogen binding to platelets (platelet-Fg) and of D-dimers were also significantly increased compared to the other patients. Levels 48xa0h after ICU admission no longer differed between the two patient groups. Platelet-Fg % was an independent predictor of sepsis (Pu2009=u20090.0031). By ROC curve analysis, cutoff point for Platelet-Fg (AUCu2009=u20090.75) was 50%. In patients with a SOFA cutoff of 8, the risk of sepsis reached 87% when Platelet-Fg levels were above 50%. Patients with sepsis had longer ICU and hospital stays and higher death rate.ConclusionsPlatelet-bound fibrinogen levels assayed by flow cytometry within 24xa0h of ICU admission help identifying critically ill patients at risk of developing sepsis.

Stress echocardiography in patients with native valvular heart disease

Valve stress echocardiography (VSE) can be performed as exercise stress echocardiography (ESE) or dobutamine stress echocardiography (DSE) depending on the patient’s clinical status, severity and type of valve disease. ESE combines exercise testing with two-dimensional grey scale and Doppler echocardiography during exercise. Thus, it provides objective assessment of symptomatic status (exercise test), as well as exercise-induced changes of a series of echocardiographic parameters (different depending on the valve disease type), which yield prognostic information in individual patients and help in a better treatment planning. DSE is useful in symptomatic patients with low-gradient aortic stenosis. It clarifies its severity and helps in assessing surgical risk in patients with severe disease and systolic dysfunction. It can be also used to test valve haemodynamics in asymptomatic patients with significant mitral stenosis unable to perform an exercise test or to test the left ventricle response, namely to test viability, in patients with ischaemic secondary mitral regurgitation. VSE has taught us that history taking, clinical examination and resting echocardiography give an ‘incomplete picture’ of the disease in patients presenting with a severe valve disease. Therefore, its use should be encouraged in such patients.

Advances in Pathophysiology of Calcific Aortic Valve Disease Propose Novel Molecular Therapeutic Targets.

Calcific Aortic Valve Disease (CAVD) is the most common heart valve disease and its incidence is expected to rise with aging population. No medical treatment so far has shown slowing progression of CAVD progression. Surgery remains to this day the only way to treat it. Effective drug therapy can only be achieved through a better insight into the pathogenic mechanisms underlying CAVD. The cellular and molecular events leading to leaflets calcification are complex. Upon endothelium cell damage, oxidized LDLs trigger a proinflammatory response disrupting healthy cross-talk between valve endothelial and interstitial cells. Therefore, valve interstitial cells transform into osteoblasts and mineralize the leaflets. Studies have investigated signaling pathways driving and connecting lipid metabolism, inflammation and osteogenesis. This review draws a summary of the recent advances and discusses their exploitation as promising therapeutic targets to treat CAVD and reduce valve replacement.

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU) for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28- and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 5-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

Dusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner

Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel outgrowth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice developed larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour-promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the presence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demonstrates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs.

Variations of circulating cardiac biomarkers during and after anthracycline-containing chemotherapy in breast cancer patients

BackgroundOver time, the chance of cure after the diagnosis of breast cancer has been increasing, as a consequence of earlier diagnosis, improved diagnostic procedures and more effective treatment options. However, oncologists are concerned by the risk of long term treatment side effects, including congestive heart failure (CHF).MethodsIn this study, we evaluated innovative circulating cardiac biomarkers during and after anthracycline-based neoadjuvant chemotherapy (NAC) in breast cancer patients. Levels of cardiac-specific troponins T (cTnT), N-terminal natriuretic peptides (NT-proBNP), soluble ST2 (sST2) and 10 circulating microRNAs (miRNAs) were measured.ResultsUnder chemotherapy, we observed an elevation of cTnT and NT-proBNP levels, but also the upregulation of sST2 and of 4 CHF-related miRNAs (miR-126-3p, miR-199a-3p, miR-423-5p, miR-34a-5p). The elevations of cTnT, NT-proBNP, sST2 and CHF-related miRNAs were poorly correlated, suggesting that these molecules could provide different information.ConclusionsCirculating miRNA and sST2 are potential biomarkers of the chemotherapy-related cardiac dysfunction (CRCD). Nevertheless, further studies and long-term follow-up are needed in order to evaluate if these new markers may help to predict CRCD and to identify the patients at risk to later develop CHF.

Potential diagnostic biomarkers of Ulcerative colitis-associated colorectal dysplasia

1GIGA-R, ULiège, Translational Gastroenterology, Liège, Belgium, 2CHU de Liège, HepatoGastroenterology and Digestive oncology, Liège, Belgium, 3CHU de Liège, Pathological anatomy and cytology, Liège, Belgium, 4GIGA proteomic facility, ULiège, Liège, Belgium, 5ULiège, Laboratory of mass spectrometry, Chemistry, Liège, Belgium, 6GIGA-R, ULiège, Laboratory of Thrombosis and Hemostasis, Liège, Belgium, 7ULiège, Mammalian cell culture laboratory, Liège, Belgium, 8CHU de Liège, Abdominal Surgery Department, Liège, Belgium, 9CHC de Liège, Gastroenterology, Liège, Belgium, 10CHR Citadelle de Liège, Gastroenterology and Digestive oncology, Liège, Belgium

Can blood biomarkers help predicting outcome in transcatheter aortic valve implantation

Transcatheter aortic valve implantation (TAVI) has become the method of choice for patients with severe aortic valve stenosis, who are ineligible or at high risk for surgery. In this high risk patient population, early and late mortality and rehospitalization rates after TAVI are still relatively high. In spite of recent improvements in procedural TAVI, and establishment of risk models for poor outcome, determining individual risk remains challenging. In this context, current data from several small studies strongly suggest that blood biomarkers of myocardial injury, cardiac mechanical stretch, inflammation, and hemostasis imbalance might play an important role by providing informations on patient risk at baseline, and postprocedural progression of patient clinical conditions from days up to years post-TAVI. Although the role of biomarkers for predicting survival post-TAVI remains to be validated in large randomized studies, implementing biomarkers in clinical practice might improve risk stratification, thereby further reducing TAVI-associated morbidity and mortality.

Prosthetic Aortic Valves: Challenges and Solutions.

Aortic Valve Disease (AVD) is the most common Valvular Heart Disease (VHD), affecting millions of people worldwide. Severe AVD is treated in most cases with prosthetic aortic valve replacement, which involves the substitution of the native aortic valve with a prosthetic one. In this review we will discuss the different types of prosthetic aortic valves available for implantation and the challenges faced by patients, medical doctors, researchers and manufacturers, as well as the approaches that are taken to overcome them.

Treating cardiovascular complications of radiotherapy: a role for new pharmacotherapies

ABSTRACT Introduction: Available data indicate that survivors of breast cancer and Hodgkin lymphoma who received mediastinal radiotherapy are at increased risk of developing radiation-induced cardiovascular diseases (RICVD) one or two decades after treatment. Although the risk with modern radiation treatment is likely to be lower in these patient groups, cardiotoxicity is still observed in a subset of patients. In addition, radiation-associated cardiovascular complications can, in the future, extend to other groups of cancer patients who are treated for tumors that are localized near the heart. Areas covered: The authors briefly describe the most commonly observed types of RICVD. They then present an overview of preclinical animal and cellular models that have been used to investigate the mechanisms underlying RICVD pathophysiology. The beneficial effects of available drugs, and potential targets for new molecules are also reported. Expert opinion: There is a need to develop cardio-oncological programs and pharmacotherapies specifically targeting RICVD. Beyond statins, ACE inhibitors, anti-inflammatory and antioxidant agents, preclinical studies indicate that TGFβ receptor I inhibitors, Sestrin2 inducers, recombinant neuregulin-1 and miR-21 inhibitors might represent novel promising strategies. In order to properly determine the optimal therapeutic index for these molecules, in vivo models combining cancer and RICVD should be envisioned.