Système sérotoninergique et cœur : aspect fondamentaux et modifications dans la cardiopathie du rétrécissement aortique chez l'homme

La sérotonine est une monoamine biogène, largement décrite et étudiée pour sa synthèse et ses effets au niveau du système nerveux central (SNC). Elle est synthétisée en deux étapes enzymatiques grâce à une hydroxylase du tryptophane (Tph) et la décarboxylase des acides aminés aromatiques (LAAD). Au sein du SNC, l'enzyme présente est la Tph2; en périphérie, la sérotonine est synthétisée massivement au niveau des cellules entérochromaffines intestinales par la Tph1, puis elle est stockée dans les granules plaquettaires. De récents travaux ont montré que cette sérotonine n'avait pas uniquement ces deux lieux de synthèse mais également, les deux enzymes ont été retrouvées dans d'autre type tissulaire comme l'os et le poumon. La première partie de ce travail a été la mise en évidence d'une synthèse intracardiaque de sérotonine. Par des approches in vitro et in vivo nous avons montré la présence de la LAAD dans l'endothélium vasculaire cardiaque et son rôle dans la synthèse locale de sérotonine. Le taux de sérotonine synthétisée de novo dans le tissu cardiaque aurait un rôle dans la phosphorylation d'une synthétase de l'oxyde nitrique (NOS) et dans la libération de NO, puissant agent vasodilatateur. Par conséquent, la LAAD endothéliale et la sérotonine cardiaque sembleraient avoir un rôle dans la régulation physiologique de la fonction cardiaque. La deuxième partie de ce travail a consisté à étudier le rôle et l'influence de la sérotonine dans l'hypertrophie cardiaque par surcharge de pression ventriculaire chez le rongeur grâce au modèle de constriction de l'aorte transverse (TAC), et chez l'Homme dans la pathologie du rétrécissement aortique (RAo). * Les expérimentations animales ont été menées chez des souris génétiquement invalidées pour la Tph1. Ces animaux, déficients en sérotonine circulante libre et plaquettaire, ont subi une TAC et l'obstacle à l'éjection du sang a provoqué une surcharge ventriculaire gauche et une hypertrophie cardiaque. Les mesures des paramètres fonctionnels, réalisées par échocardiographie, analyse morphométrique, moléculaire et histologique ont montré que la TAC provoque une hypertrophie chez les souris Tph1-/- comme chez les souris sauvages. Cependant, l'hypertrophie évolue vers une cardiopathie dilatative chez les souris Tph1-/-. Ce phénomène, ainsi que la fibrose du muscle cardiaque, peuvent être prévenus lorsque les souris Tph1-/- sont supplémentées par le précurseur de la sérotonine, le 5-HTP. Ces données indiquent que la sérotonine ou son précurseur aurait un rôle dans l'hypertrophie adaptative compensatoire protectrice et limiterait l'évolution vers la cardiomyopathie pathologique. * Le RAo est la valvulopathie la plus fréquente chez l'Homme adulte et à fortiori chez la personne âgée. Cette pathologie met en place des phénomènes de fibrose et de calcification de la valve aortique ce qui constitue un obstacle à l'éjection du sang par le ventricule gauche, le plus souvent l'issue est l'insuffisance cardiaque. La dernière partie de ce manuscrit présente les résultats de la recherche biomédicale SERAOPI. Dans cette étude, 15 volontaires sains et 30 patients atteints de RAo de sévérité variable, ont été inclus. Une échocardiographie et des dosages des taux de sérotonine plasmatique artériel radial et aortique pour les patients subissant une coronarographie ainsi que le produit de dégradation de la sérotonine, le 5Hydroxy Indole Acétique Acide (5HIAA) ont été réalisés. Il a également était mesuré les degrés d'activation des plaquettes pour mettre en relation la sérotonine et signer éventuellement l'origine plaquettaire. Les résultats ont démontré que l'activation plaquettaire ainsi que la sérotonine et la 5HIAA plasmatiques ont des niveaux augmentés dans la pathologie du RAo. L'ensemble de ces résultats suggère que la sérotonine, relarguée en partie par les plaquettes et/ou produite par l'endothélium coronarien, participe à la régulation de la fonction cardiaque en situation physiologique et dans l'hypertrophie cardiaque par surcharge de pression ventriculaire.Serotonin (HT) is a biogenic monoamine, widely described and studied for its central nervous system (CNS) synthesis and effects. 5HT is synthesized in two steps enzymatic through a tryptophan hydroxylase (Tph) and an aromatic amino acids decarboxylase (LAAD). At the periphery, serotonin is massively synthesized by intestinal enterochromaffin cells by the Tph1, and then 5HT is stored in granules platelet. Recent works have shown that the serotonin has not only these two places of synthesis, enzymes can be isolated in another type of tissue as lung or bone. The first part of this work has been highlighting a 5HT intracardiac synthesis. "In vitro" and "in vivo" approaches showed the presence of the LAAD enzyme in cardiac vascular endothelium and its 5HT local production. Synthesized "de novo" in cardiac tissue, 5HT has a role of synthase nitric oxide (NOS) phosphorylation and a release of NO, powerful vasodilator agent. The cardiac endothelial LAAD and 5HT would appear to have a role in cardiac physiology. The second part of this work was to study the role and the influence of serotonin in cardiac hypertrophy by ventricular pressure overload in the rodent model of transverse aortic constriction (TAC) and in Human in the aortic stenosis pathology (AS). Animal experiments have been conducted in mice Knock Out for the Tph1. These animals, with low circulating free and platelet serotonin, suffered a TAC and developed a left ventricular overload and cardiac hypertrophy. The measure of the functional parameters, by echocardiography, morphometric analysis, molecular and histological approaches showed that the TAC causes hypertrophy in mice Tph1-/-as in wild mice. However, hypertrophy progresses to dilatative cardiomyopathy disease in mice Tph1-/-. This watching, and heart fibrosis, can be prevented when mice Tph1-/ - are supplemented by the serotonin precursor, 5 - Hydroxy Tryptophane (5HTP). These data indicate that serotonin, or its precursor would have a role in adaptive compensatory protective hypertrophy and seems to limit a pathological cardiomyopathy evolution. AS is the commonest valvular disease in Human adult and in the elderly person. This pathology shows fibrosis and calcification of the aortic valve which is an obstacle to blood ventricle ejection, frequently heart chronic failure is the issue. The last part of this manuscript presents the results of biomedical research SERAOPI. In this study, 15 healthy volunteers (without cardiac, depressive and platelet pathology, more than 50 years old and without medicine that change serotonin level) and 30 patients with different AS severity (with AS but without coronary, depressive and platelet desease, more than 50 years old and without medicine that change serotonin level) were included for echocardiography, aortic and radial arterial plasma serotonin levels assay, as the serotonin degradation product, the 5 Hydroxy Indole Acetic Acid (5HIAA). Platelets activation degrees also were measured to probably sign serotonin origin. It would seem that plasmatic serotonin and the 5HIAA increase in the RAo pathology as platelet activation, and in proportion to the aortic stenosis valve severity. These results suggest that plasma 5HT coming from circulating platelet or neo-synthesized in cardiac tissue appears to be involved in cardiac physiology and cardiac hypertrophic pathology due to ventricular overload

Evaluation of polyelectrolyte complex-based scaffolds for mesenchymal stem cell therapy in cardiac ischemia treatment

Three-dimensional (3D) scaffolds hold great potential for stem cell-based therapies. Indeed, recent results have shown that biomimetic scaffolds may enhance cell survival and promote an increase in the concentration of therapeutic cells at the injury site. The aim of this work was to engineer an original polymeric scaffold based on the respective beneficial effects of alginate and chitosan. Formulations were made from various alginate/chitosan ratios to form opposite-charge polyelectrolyte complexes (PECs). After freeze-drying, the resultant matrices presented a highly interconnected porous microstructure and mechanical properties suitable for cell culture. In vitro evaluation demonstrated their compatibility with mesenchymal stell cell (MSC) proliferation and their ability to maintain paracrine activity. Finally, the in vivo performance of seeded 3D PEC scaffolds with a polymeric ratio of 40/60 was evaluated after an acute myocardial infarction provoked in a rat model. Evaluation of cardiac function showed a significant increase in the ejection fraction, improved neovascularization, attenuated fibrosis as well as less left ventricular dilatation as compared to an animal control group. These results provide evidence that 3D PEC scaffolds prepared from alginate and chitosan offer an efficient environment for 3D culturing of MSCs and represent an innovative solution for tissue engineering

Evaluation of polyelectrolyte complex-based scaffolds for mesenchymal stem cell therapy in cardiac ischemia treatment

b s t r a c t Three-dimensional (3D) scaffolds hold great potential for stem cell-based therapies. Indeed, recent results have shown that biomimetic scaffolds may enhance cell survival and promote an increase in the concentration of therapeutic cells at the injury site. The aim of this work was to engineer an original polymeric scaffold based on the respective beneficial effects of alginate and chitosan. Formulations were made from various alginate/chitosan ratios to form opposite-charge polyelectrolyte complexes (PECs). After freeze-drying, the resultant matrices presented a highly interconnected porous microstructure and mechanical properties suitable for cell culture. In vitro evaluation demonstrated their compatibility with mesenchymal stell cell (MSC) proliferation and their ability to maintain paracrine activity. Finally, the in vivo performance of seeded 3D PEC scaffolds with a polymeric ratio of 40/60 was evaluated after an acute myocardial infarction provoked in a rat model. Evaluation of cardiac function showed a significant increase in the ejection fraction, improved neovascularization, attenuated fibrosis as well as less left ventricular dilatation as compared to an animal control group. These results provide evidence that 3D PEC scaffolds prepared from alginate and chitosan offer an efficient environment for 3D culturing of MSCs and represent an innovative solution for tissue engineering

Primo-prescription de fluoroquinolones dans les services de neurologie et réévaluation à 48-72 heures : une expérience du Centre hospitalier universitaire de Toulouse

RésuméObjectif : L’objectif de l’étude est de connaitre les pratiques de prescriptions des fluoroquinolones dans des services de neurologie en France, en évaluant la réévaluation à 48-72 heures de la mise en place d’une telle antibiothérapie.Mise en contexte : Les fluoroquinolones sont des antibiotiques largement prescrits. De nombreuses démarches permettent d’améliorer la qualité de la prescription des antibiotiques, notamment la réévaluation de l’antibiothérapie à 48-72 heures.Résultats : Cette étude descriptive et prospective, portant sur le recueil des prescriptions informatisées de fluoroquinolones, a été réalisée dans les services de neurologie pendant une période de trois mois. En tout, 23 prescriptions de fluoroquinolones ont été sélectionnées. Dix-neuf (83 %) des infections traitées étaient nosocomiales et 16 (70 %) étaient probabilistes (ou empiriques). La médiane des valeurs de la protéine C-réactive était de 23,8 mg/ml (intervalle : 0,7 à 69,8 mg/ml) et celle des taux de leucocytes était de 9,6 g/l (intervalle de 7,3 à 19,7 g/l). La durée moyenne d’antibiothérapie était de six jours. La réévaluation de l’antibiothérapie à 48-72 heures était mentionnée dans le dossier du patient dans 39 % des cas.Conclusion : Il convient de réserver l’usage des fluoroquinolones à des infections documentées pour diminuer le risque de résistance envers cette classe d’antibiotiques. La création de protocoles de prise en charge probabiliste (ou empirique) d’infections nosocomiales peut être envisagée. La réévaluation de l’antibiothérapie à 48-72 heures est primordiale et doit être généralisée. L’informatisation de ces étapes peut aider à y parvenir.AbstractObjective: The objective of this study was to explore fluoroquinolone prescribing practices in neurology departments in France, with a focus on the reassessment at 48 to 72 hours after initiation of the antibiotic therapy.Background: Fluoroquinolones are widely prescribed antibiotics. There are many approaches for improving the quality of antibiotic prescribing. One of them is a reassessment of the antibiotic therapy at 48 to 72 hours.Results: This descriptive, prospective study based on a compilation of computerized prescriptions for fluoroquinolones was carried out in neurology departments over a 3-month period. Twenty-three fluoroquinolone prescriptions were selected. Nineteen (83%) of the treated infections were nosocomial, and 16 (70%) were empirical. The median C-reactive protein level was 23.8 mg/mL (range: 0.7 to 69.8 mg/mL), and the median leucocyte count was 9.6 g/l (range: 7.3 to 19.7 g/l). The mean duration of antibiotic therapy was six days. A reassessment of the antibiotic therapy at 48 to 72 hours was mentioned in the patient’s chart in 39% of the cases.Conclusion: The use of fluoroquinolones should be reserved for targeted infections to reduce the risk of resistance to this class of antibiotics. Consideration might be given to creating protocols for the empirical management of nosocomial infections. Reassessing antibiotic therapy at 48 to 72 hours is essential and should be generalized. Computerizing these steps could help achieve this

From hospitalisation to primary care: integrative model of clinical pharmacy with patients implanted with a PICC line—research protocol for a prospective before–after study

Introduction Clinical pharmacy improves patient safety and secures drug management using information, education and good clinical practices. However, medical device management is still unexplored, and proof of effectiveness is needed. A PICC line (peripherally inserted central catheter) is a medical device for infusion. It accesses the central venous system after being implanted in a peripheral vein. However, complications after implantation often interfere with smooth execution of the treatment. We hypothesise that clinical pharmacy for medical devices could be as effective as clinical pharmacy for medications. The main objective is to assess the effectiveness of clinical pharmacy activities on the complication rate after PICC line implantation.Methods and analysis This is a before–after prospective study. The study will begin with an observational period without clinical pharmacy activities, followed by an interventional period where pharmacists will intervene on drug and medical device management and provide personalised follow-up and advice. Sixty-nine adult patients will be recruited in each 6-month period from all traditional care units. The main inclusion criteria will be the implantation of a PICC line. The primary outcome is the decrease in the number of complications per patient and per month. Secondary outcomes are the consultation and hospital readmission rates, the acceptance rate of pharmaceutical interventions, the patients’ quality of life, the direct hospital induced or avoided costs and the participants’ satisfaction. Data will be collected using case report forms during hospitalisation and telephone follow-up after discharge. The analysis will compare these criteria during the two periods.Ethics and dissemination The study has received the approval of our Ethics Committee (Clermont-Ferrand Southeast VI, France, number AU1586). Results will be made available to the patients or their caregivers, the sponsor and other researchers when asked, as described in the consent form.Trial registration number NCT04359056

Mechanical Thrombectomy with Intravenous Thrombolysis versus Thrombolysis Alone for the Treatment of Stroke: A Systematic Review of Economic Evaluations

International audienceMechanical thrombectomy has revolutionized the management of stroke by improving the recanalization rates and reducing deleterious consequences. It is now the standard of care despite the high financial cost. A considerable number of studies have evaluated its cost effectiveness. Therefore, this study aimed to identify economic evaluations of mechanical thrombectomy with thrombolysis compared with thrombolysis alone to provide an update of existing evidence, focusing on the period after proof of effectiveness of mechanical thrombectomy. Twenty-one studies were included in the review: 18 were model-based economic evaluations to simulate long-term outcomes and costs, and 19 were conducted in high-income countries. Incremental cost-effectiveness ratios ranged from -$5,670 to$74,216 per quality-adjusted life year. Mechanical thrombectomy is cost-effective in high-income countries and in the populations selected for clinical trials. However, most of the studies used the same data. There is a lack of real-world and long-term data to analyze the cost effectiveness of mechanical thrombectomy in treating the global burden of stroke

Role of endothelial AADC in cardiac synthesis of serotonin and nitrates accumulation.

Serotonin (5-HT) regulates different cardiac functions by acting directly on cardiomyocytes, fibroblasts and endothelial cells. Today, it is widely accepted that activated platelets represent a major source of 5-HT. In contrast, a supposed production of 5-HT in the heart is still controversial. To address this issue, we investigated the expression and localization of 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and L-aromatic amino acid decarboxylase (AADC) in the heart. We also evaluated their involvement in cardiac production of 5-HT. TPH1 was weakly expressed in mouse and rat heart and appeared restricted to mast cells. Degranulation of mast cells by compound 48/80 did not modify 5-HT cardiac content in mice. Western blots and immunolabelling experiments showed an abundant expression of AADC in the mouse and rat heart and its co-localization with endothelial cells. Incubation of cardiac homogenate with the AADC substrate (5-hydroxy-L-tryptophan) 5-HTP or intraperitoneal injection of 5-HTP in mice significantly increased cardiac 5-HT. These effects were prevented by the AADC inhibitor benserazide. Finally, 5-HTP administration in mice increased phosphorylation of aortic nitric oxide synthase 3 at Ser (1177) as well as accumulation of nitrates in cardiac tissue. This suggests that the increase in 5-HT production by AADC leads to activation of endothelial and cardiac nitric oxide pathway. These data show that endothelial AADC plays an important role in cardiac synthesis of 5-HT and possibly in 5-HT-dependent regulation of nitric oxide generation

Cardiac fibroblasts regulate sympathetic nerve sprouting and neurocardiac synapse stability.

International audienceSympathetic nervous system (SNS) plays a key role in cardiac homeostasis and its deregulations always associate with bad clinical outcomes. To date, little is known about molecular mechanisms regulating cardiac sympathetic innervation. The aim of the study was to determine the role of fibroblasts in heart sympathetic innervation. RT-qPCR and western-blots analysis performed in cardiomyocytes and fibroblasts isolated from healthy adult rat hearts revealed that Pro-Nerve growth factor (NGF) and pro-differentiating mature NGF were the most abundant neurotrophins expressed in cardiac fibroblasts while barely detectable in cardiomyocytes. When cultured with cardiac fibroblasts or fibroblast-conditioned medium, PC12 cells differentiated into/sympathetic-like neurons expressing axonal marker Tau-1 at neurites in contact with cardiomyocytes. This was prevented by anti-NGF blocking antibodies suggesting a paracrine action of NGF secreted by fibroblasts. When co-cultured with cardiomyocytes to mimic neurocardiac synapse, differentiated PC12 cells exhibited enhanced norepinephrine secretion as quantified by HPLC compared to PC12 cultured alone while co-culture with fibroblasts had no effect. However, when supplemented to PC12-cardiomyocytes co-culture, fibroblasts allowed long-term survival of the neurocardiac synapse. Activated fibroblasts (myofibroblasts) isolated from myocardial infarction rat hearts exhibited significantly higher mature NGF expression than normal fibroblasts and also promoted PC12 cells differentiation. Within the ischemic area lacking cardiomyocytes and neurocardiac synapses, tyrosine hydroxylase immunoreactivity was increased and associated with local anarchical and immature sympathetic hyperinnervation but tissue norepinephrine content was similar to that of normal cardiac tissue, suggesting depressed sympathetic function. Collectively, these findings demonstrate for the first time that fibroblasts are essential for the setting of cardiac sympathetic innervation and neurocardiac synapse stability. They also suggest that neurocardiac synapse functionality relies on a triptych with tight interaction between sympathetic nerve endings, cardiomyocytes and fibroblasts. Deregulations of this triptych may be involved in pathophysiology of cardiac diseases

First evidence of increased plasma serotonin levels in Tako-Tsubo cardiomyopathy.

International audienceBACKGROUND: There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS). METHODS AND RESULTS: Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (3.9 ± 4.6, P = 0.02 versus control; 5.7 ± 5.6, P = 0.001 versus control; and 1 ± 0.4 ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (P = 0.33). CONCLUSION: This finding suggests that serotonin could participate to the pathophysiology of TTC

Inhibition of cardiac 5-HT synthesis <i>in vivo</i> in presence of the AADC inhibitor benserazide.

<p>(A) Mice were pretreated with benserazide (100 mg/kg ip) or saline 30 min before 5-HTP administration (20 mg/kg ip) and they were sacrified 30 min after the last injection. 5-HT and 5-HTP were measured in heart. (B) Mice were treated only with benserazide (100 mg/kg ip) or saline 30 min before euthanasia. 5-HT and 5-HTP were measured in heart and 5-HTP in plasma. Values are means ± SEM (<i>n</i> = 8–10 to each group). *<i>P</i><0.05; **<i>P</i><0.001 vs. saline.</p