Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation.</p> <p>Methods</p> <p>We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE).</p> <p>Results</p> <p>Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68⁺/vimentin⁺cells.</p> <p>Conclusion</p> <p>Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.</p

Awareness campaigns of atrial fibrillation as an opportunity for early detection by pharmacists: an international cross-sectional study

Atrial fibrillation (AF) accounts for up to one third of strokes, one of the lead mortality causes worldwide. The European Society of Cardiology guidelines recommend opportunistic screening as a means to increase the odds of early detection and institution of appropriate treatment according to risk factors identified. However, in most countries there are various barriers to effective uptake of screening, including low awareness. The Atrial Fibrillation Association is a patient association engaged with raising awareness of AF. Establishing a partnership with the International Pharmacists for Anticoagulation Care Taskforce, we set as goals to test a model for raising awareness of AF involving pharmacists globally; and to identify barriers and enablers to its implementation. A cross-sectional study was conducted during the Arrhythmia Alliance World Heart Rhythm Week. Pharmacists from 10 countries invited individuals (≥ 40 years; without anticoagulation therapy of AF) to participate in the awareness campaign. Participants agreeing were engaged in the early detection of AF (EDAF) using pulse palpation. Individuals with rhythm discrepancies were referred and prospectively assessed to have information on the proportion of confirmed diagnosis, leading to estimate the detection rate. Interviews with country coordinators explored barriers and enablers to implementation. The study involved 4193 participants in the awareness campaign and 2762 in the EDAF event (mean age 65.3 ± 13.0), of whom 46.2% individuals were asymptomatic, recruited across 120 sites. Most common CHA2DS2-VASc risk factor was hypertension. Among 161 patients referred to physician, feedback was obtained for 32 cases, of whom 12 new arrhythmia diagnoses were confirmed (5 for AF, 2 for atrial flutter), all among elders (≥ 65 years). Qualitative evaluation suggested a local champion to enable pharmacists’ success; technology enhanced engagement amongst patients and increased pharmacists’ confidence in referring to physicians; interprofessional relationship was crucial in success. This study suggests pharmacists can contribute to greater outreach of awareness campaigns. Effective communication pathways for inter-professional collaboration were suggested enablers to gain full benefits of EDAF

Non vasodilator therapeutic innovations in pulmonary arterial hypertension

L’hypertension artérielle pulmonaire (HTAP) correspond à un groupe de maladies qui se caractérise par une obstruction vasculaire suite à une vasoconstriction excessive, une prolifération cellulaire et la création de thromboses in situ, conduisant à une augmentation progressive des résistances vasculaires pulmonaires puis au décès. De nombreuses avancées dans la prise en charge de l’HTAP ont été réalisées ces dernières années avec la mise à disposition de médicaments principalement vasodilatateurs. Cependant, aucun de ces médicaments n’est curatif de la maladie témoignant de la nécessité à obtenir de nouvelles thérapeutiques. Des molécules axant leur effet sur la lutte contre la prolifération cellulaire liée à l’activation des récepteurs à tyrosine-kinases (RTK) ou le stress oxydant (SO) paraissent aujourd’hui comme de potentielles innovations thérapeutiques dans l’HTAP. Cependant, à l’heure actuelle, les données sur le SO dans l’HTAP sont trop peu détaillées pour cibler correctement cette voie physiopathologique. De même, les inhibiteurs de tyrosine-kinases ont montré un bénéfice dans la prise en charge de l’HTAP mais associé à des effets indésirables graves tels qu’une toxicité cardiaque. Dans ce travail, nous avons approfondi le mécanisme d’action du SO dans la physiopathologie de l’HTAP et complété l’identification des RTK dans le remodelage vasculaire pulmonaire afin de permettre la mise au point de thérapeutiques efficaces avec un rapport bénéfice risque favorable pour le patient.Pulmonary arterial hypertension (PAH) corresponds to a group of diseases characterized by a vascular obstruction due to vasoconstriction, cellular proliferation and in situ thrombosis, leading to a progressive increase in pulmonary vascular resistances. New knowledge in the PAH management were performed in the last few years, specifically for vasodilators. However, none of those treatments cure the disease and new drugs are still needed. Molecules targeting cellular proliferation induced by tyrosine kinases receptors (TKR) activation or oxidative stress (OS) seem to be potential therapeutic innovations. However, knowledge on OS in PAH is not enough accomplished in PAH to target accurately this pathophysiologic pathway. Similarly, tyrosine kinase inhibitors have shown efficacy in PAH management but associated with severe adverse events as cardiac toxicity. In this study, mechanism of action of OS in pathophysiology of PAH was detailed and identification of TKR involved in vascular remodeling was completed in order to find efficient therapeutics with a favorable risk benefit ratio for PAH patient

Optimisation de la prise en charge thérapeutique du patient souffrant d'hypertension artérielle pulmonaire (projet Pilote de développement professionnel continu OP'TEAM)

PARIS-BIUP (751062107) / SudocSudocFranceF

DI-068 Beliefs, knowledge and expectations about medicines and pharmacists in asthma and pulmonary arterial hypertension patients: preliminary results: https://ejhp.bmj.com/content/22/Suppl_1/A101.1

International audienceBackground Chronic diseases have changed the management of patients and their status, to move toward a new “patient-healthcare providers” partnership. Asthma and pulmonary arterial hypertension (PAH) are two chronic thoracic diseases with differences in terms of prevalence and drug delivery process. Little is known regarding patient’s beliefs (B), knowledge (K) and expectations (E) of their illness, medicines and healthcare providers, despite these parameters influencing their adherence, behaviour and outcomes.Purpose To gain detailed insight into B, K and E of medicines and pharmacists from asthma or PAH patients.Material and methods For this observational prospective monocentric study, an interview guide was designed and validated to perform the semi-structured interviews (SSI). Each interview was recorded and fully transcribed. An inductive approach was conducted for the remaining text to inventory verbatim. All were classified according to the key ideas to describe B, K, E for each population.Results SSI were conducted with 14 patients (5 asthma–9 PAH) (mean duration 37 ± 10 min) from December 2013 to April 2014. Medicines were perceived as a “necessity” (6 PAH–3 asthma), a “constraint” (3 PAH) or “poisons” (2 asthma). Three asthma patients didn’t perceive the necessity of corticosteroids but all judged salbutamol and terbutaline as vital. Four PAH patients noticed few people and healthcare professionals who knew PAH and its management. Pharmacists could sometimes be perceived only as “retailers” (2 PAH–3 asthma), “advisors” (3 PAH) or associated with “medicines” (2 PAH–2 asthma). Tasks of pharmacists weren’t well known and defined (5 PAH–4 asthma).Conclusion Medicines and pharmacists were perceived differently depending on asthma or PAH patients. The ignorance about “what exactly pharmacists do” makes their role ambiguous for the patients leading to difficulties in describing their expectations of pharmaceutical care. More interviews are warranted to improve the B, K, E description of our populations

Dispositif de formation d’une équipe pharmaceutique à la consultation d’accompagnement d’un patient sous traitement anticoagulant oral

Contexte : Dans le cadre de l’amélioration de la prise en charge médicamenteuse du patient sous anticoagulants oraux et de la prévention de l’iatrogénie, la pharmacie de l’hôpital Antoine Béclère a mis en pl ace, depuis 2009, des « Consultations antivitamines K (AVK) » auprès des patients hospitalisés. But : Rapporter l’élaboration et l’évaluation préliminaire d’un dispositif de formation aux consultations AVK. Matériels et méthode : Un groupe de travail de pharmaciens a élaboré un dispositif pédagogique s’articulant autour d’un apprentissage théorique (savoir déclaratif) et pratique (capacités, habiletés, aptitudes). Pour formaliser la méthode, une fiche de projet pédagogique a élaborée. Des outils de formation et d’évaluation ont été créés. Résultats : Le parcours de formation est divisé en cinq étapes : pré-évaluation des connaissances ; formation théorique reprenant contexte et points-clés de la consultation ; atelier de mise en situation patient fictif/pharmacien ; réévaluation des connaissances ; consultations pratiques en supervision directe. Trente-quatre étudiants ont suivi cette formation. La comparaison des évaluations a montré une progression individuelle significative des scores d’apprentissage. Toutes les personnes formées ont été validées après deux évaluations pratiques. L’enquête de satisfaction a montré une satisfaction de 100 % des participants. Conclusion : Au regard des résultats obtenus, un impact positif du dispositif de formation élaboré peut-être tenu comme avéré. Un programme e-learning est en cours de développement afin de systématiser la formation à ces consultations et de l’élargir à toute l’équipe pharmaceutique du groupe hospitalier Paris-Sud

Animal Model Methodology: Immunocompetent or Leucopenic Rats, Which Is the Best Results from a Model of Experimental Pneumonia due to Derepressed Cephalosporinase-Producing Enterobacter cloacae

International audienc

Investigating the association between ALK Receptor Tyrosine Kinase inhibitors and pulmonary arterial hypertension: a disproportionality analysis from the WHO pharmacovigilance database

International audienc

Échange de savoirs entre le patient et le pharmacien : une étude à méthodes mixtes pour explorer le rôle des pharmaciens dans l'éducation et le conseil aux patients dans le domaine de l'asthme et de l'hypertension artérielle pulmonaire

International audienceObjectives: To better understand the role of pharmacists in patient education and counselling: describe the perception of knowledge exchange (KE) between asthma/pulmonary arterial hypertension patients and pharmacists (hospital/community) according to four dimensions (4C-typology): Cure (C1), Care (C2); Coordination/supply chain (C3), Characteristics of the pathophysiology/disease mechanisms (C4); factors correlated with KE.Methods: A mixed-methods approach was used. Part A: data from semi-structured patient interviews were processed (thematic analysis), and a questionnaire developed. Part B: completed patient questionnaires were processed by correspondence factor analysis.Results: KE (4C-typology) was correlated with pathology, disease severity, disease duration, age, hospital/community pharmacist. Patients expected pharmacists to provide C2/C3 services. KE with pharmacists covered C1/C2/C3, and with physicians, C1/C2/C4. While patients perceived KE as a means of self-learning to improve self-care skills, the two-way nature meant it provided specific experiential information feedback to pharmacists.Conclusions: This 4C-typology provides a holistic framework for optimising the pharmacists’ role in education and counselling of patients with chronic diseases.Objectifs : Mieux comprendre le rôle des pharmaciens dans l'éducation et le conseil aux patients : décrire la perception de l'échange de savoirs (ES) entre les patients asthmatiques/hypertenseurs artériels pulmonaires et les pharmaciens (hôpital/communauté) selon quatre dimensions (typologie 4C) : Cure (C1), Soins (C2) ; Coordination/chaîne d'approvisionnement (C3), Caractéristiques de la physiopathologie/mécanismes de la maladie (C4) ; facteurs corrélés avec les ES.Méthodes : Une approche mixte a été utilisée. Partie A : les données des entretiens semi-structurés avec les patients ont été traitées (analyse thématique), et un questionnaire a été élaboré. Partie B : les questionnaires remplis par les patients ont été traités par une analyse factorielle des correspondances.Résultats : Les ES (typologie 4C) était corrélée avec la pathologie, la gravité de la maladie, la durée de la maladie, l'âge, le pharmacien hospitalier/communautaire. Les patients s'attendaient à ce que les pharmaciens fournissent des services C2/C3. Les ES avec les pharmaciens couvrait C1/C2/C3, et avec les médecins, C1/C2/C4. Alors que les patients percevaient les ES comme un moyen d'auto-apprentissage pour améliorer leurs compétences en matière de soins personnels, la nature bidirectionnelle des ES a permis de fournir un retour d'information expérientiel spécifique aux pharmaciens.Conclusions : Cette typologie 4C fournit un cadre holistique pour optimiser le rôle des pharmaciens dans l'éducation et le conseil des patients atteints de maladies chroniques