Influence de la sérotonine et de son récepteur 5-HT2A sur le remodelage ventriculaire au cours de l'insuffisance cardiaque

L'insuffisance cardiaque est une maladie circulatoire qui implique la mise en jeu de systèmes d'adaptation neuro-hormonaux participant au remodelage ventriculaire et à l'entretien de la dysfonction cardiaque. La sérotonine plasmatique et plaquettaire est augmentée chez des patients en insuffisance cardiaque, ce qui suggère une participation de cette neuro-hormone dans le remodelage ventriculaire. L'objectif de ce travail a été de préciser par une approche in vivo le rôle de la sérotonine et de son récepteur 5-HT2A sur le remodelage ventriculaire, étape déterminante de l'insuffisance cardiaque. Dans une première partie, nous nous sommes intéressés au phénotype cardiaque de souris génétiquement déficientes pour la monoamine oxydase - A (MAO-A, enzyme de dégradation de la sérotonine) qui présentent des taux élevés de sérotonine circulante. Dans cette étude nous démontrons que les souris KO MAO-A soumises à une sténose aortique présentent une augmentation des taux myocardiques de sérotonine et une exacerbation de la réponse hypertrophique sans dysfonction ventriculaire. Cette réponse hypertrophique exacerbée, ainsi que les stigmates histologiques et biologiques moléculaires qui accompagnent le remodelage ventriculaire, sont prévenus par l'administration d'un antagoniste sélectif du récepteur 5-HT2A de la sérotonine. Dans une deuxième partie, nous nous sommes intéressés au rôle du récepteur 5- HT2A dans la phase de transition entre hypertrophie concentrique compensatrice et hypertrophie excentrique avec dysfonction ventriculaire, après sténose aortique, chez des souris sauvages C57/Bl6. Dans cette étude, nous montrons que l'inhibition sélective du récepteur 5-HT2A par le M100907 prévient l'apparition d'une hypertrophie concentrique après sténose aortique mais précipite l'évolution vers l'insuffisance cardiaque. Ces données suggèrent que le récepteur 5-HT2A pourrait exercer un effet protecteur au cours de la surcharge barométrique en favorisant l'hypertrophie compensatrice et en prévenant la dysfonction ventriculaire. En se basant sur les résultats précédents, nous avons développé un essai clinique visant à mesurer la corrélation entre les niveaux circulants de sérotonine et la réponse hypertrophique du myocarde au cours du rétrécissement aortique serré chez l'homme. Cette étude est financée par la région Midi-Pyrénées. Nos travaux démontrent que la sérotonine, via son récepteur 5-HT2A, participe au remodelage ventriculaire au cours de la surcharge barométrique en favorisant l'hypertrophie myocardique compensatrice.Heart failure is a systemic disease involving neuro-hormonal adaptive systems that participate to ventricular remodeling and maintain cardiac dysfunction. Plasmatic and platelets serotonin are increased in patients with heart failure suggesting a role during ventricular remodeling. The aim of this work was to specify in vivo the role of serotonin and its receptor 5-HT2A during ventricular remodeling that is a determinant step of heart failure. In a first part, we studied the cardiac phenotype of mice knock-out for monoamine oxidase – A (MAO – A, serotonin degradation enzyme) which display elevated circulating levels of serotonin. With this study, we showed that mice knock-out for MAO – A display elevated intramyocardial serotonins levels with exacerbated hypertrophic response without myocardial dysfunction. This increased hypertrophic response and the histological and molecular signs of ventricular remodeling are prevented by selective 5-HT2A receptor antagonist administration. In a second part, we explored the role of the 5-HT2A receptor during the transition phase between adapted concentric hypertrophic response and non-adapted eccentric hypertrophic response with ventricular dysfunction after aortic banding in C57/Bl6 wild type mice. In this study, we showed that selective 5-HT2A receptor antagonist M100907 administration prevents concentric hypertrophic response after aortic banding but precipitates evolution to heart failure. These results suggest that 5-HT2A receptor could have a protecting effect during pressure overload by favoring adapted hypertrophy and preventing from ventricular dysfunction. From these results, we designed a clinical trial, funded by Conseil Régional Midi-Pyrénées, aim to assess correlation between serotonin circulating levels and myocardial hypertrophic response during aortic stenosis in human. Findings show that the serotonin and its 5-HT2A receptor participate to ventricular remodeling during pressure overload by favoring adapted myocardial hypertrophic response

Alginate Scaffolds for Mesenchymal Stem Cell Cardiac Therapy: Influence of Alginate Composition

Despite the success of alginate scaffolds and mesenchymal stem cells (MSCs) therapy in cardiac failure treatment, the impact of the physicochemical environment provided by alginate matrices on cell behavior has never been investigated. The purpose of this work was double: to determine the alginate composition influence on (1) encapsulated rat MSC viability, paracrine activity, and phenotype in vitro and (2) cardiac implantability and in vivo biocompatibility of patch shape scaffolds. Two alginates, differing in composition and thus presenting different mechanical properties when hydrogels, were characterized. In both cases, encapsulated MSC viability was maintained at around 75%, and their secretion characteristics were retained 28 days postencapsulation. In vivo study revealed a high cardiac compatibility of the tested alginates: cardiac parameters were maintained, and rats did not present any sign of infection. Moreover, explanted hydrogels appeared surrounded by a vascularized tissue. However, scaffold implantability was highly dependent on alginate composition. G-type alginate patches, presenting higher elastic and Young moduli than M-type alginate patches, showed a better implantation easiness and were the only ones that maintained their shape and morphology in vivo. As a consequence of alginate chemical composition and resulting hydrogel structuration, G-type alginate hydrogels appear to be more adapted for cardiac implantation

Takotsubo Cardiomyopathy in a Squash Player

Takotsubo cardiomyopathy is usually described following acute emotional stress. We report here the case of a 48-year-old woman admitted for acute coronary syndrome after an intensive squash match. Diagnosis of Takotsubo cardiomyopathy due to acute physical stress was suspected in presence of normal coronary arteries and transitory left ventricular dysfunction with typical apical ballooning. Cardiac magnetic resonance imaging confirmed regional wall-motion abnormalities and was helpful in excluding myocardial infarction diagnosis. During squash the body is subject to sudden and vigorous demands inducing a prolonged and severe workload on the myocardium

0400: Degenerative calcific mitral stenosis in patients referred for high surgical risk aortic stenosis: detection and quantification by multi-detector computed tomography

BackgroundMitral annular calcifications (MAC) is a common finding in elder patients referred for transcatheter aortic valve implantation (TAVI), sometimes responsible of significant degenerative calcified mitral stenosis (CaMS), but prevalence of both is poorly defined. Multidectector computed tomography (MDCT) allows fine quantification of calcifications and is a reliable tool in rheumatic mitral stenosis, but its contribution in CaMS remains unknown. Our objective was to estimate prevalence of MAC and CaMS in patients referred for TAVI using MDCT, and determine morphological factors leading from MAC to CaMS.Methods and resultsA cohort of 346 consecutive patients referred for TAVI evaluation was screened by MDCT for MAC. One hundred and seventy four patients were positive for MAC. Among these patients, 165 patients had mitral valve area (MVA) assessable by MDCT planimetry (mean age 84 years). Analysis by segment revealed calcifications on: A1 30.9%, A2 29.1%, A3 42.4%, P1 56.4%, P2 78.8%, P3 69.7%. Mean mitral calcification volume and MVA were 1020±1398mm3 and 246±90mm 2, respectively. CaMS were severe, moderate and mild in 2.4%, 21.8% and 9.7% patients, respectively. Correlation between mitral calcification volume and MVA was significant but moderate (r=–0.433). On multivariate analysis, MVA was independently linked to mitral calcification volume, aortic annular area and specific patterns of mitral leaflet calcification underlining the role of A2 (AUC 0.81). Interobserver reproducibility of MVA was high (ICC 0.935).ConclusionsMDCT allows detailed assessment of MAC in TAVI populations, demonstrating high prevalence, and quantification of CaMS with high reproducibility. Mitral analysis should become routine during MDCT screening before TAVI as it may significantly alter the therapeutic strategy

058 The ongoing MESAMI translational research program

PurposeDespite the improvement of pharmacological and surgical therapies, the mortality related to ischemic heart failure remains high. During the last years, bone marrow-mesenchymal stem cell (BM-MSC) therapy has been proposed as a novel approach for the prevention and therapy of heart failure. Intramyocardial injection allows concentration of grafted cells within the injured zone. However, a major problem of with intraparenchymal route of administration is the early death of most of grafted cells. The goal of the MESAMI program is to evaluate the effect of intramyocardial administration of BM-MSC preconditioned or not with the pineal hormone melatonin in ischemic cardiomyopathy.Methods and ResultsOur preclinical investigations have designed a preconditioning strategy of BM-MSCs with the melatonin that significantly increases survival and efficacy of grafted cells in animal models of myocardial ischemia. Melatonin treatment significantly ameliorates the beneficial effects of BM-MSC on the recovery of cardiac function. In the mean time, we started a phase I clinical trial in patients with severe ischemic cardiomyopathy and no option of revascularization, using the NOGA XP system to guide injections into the myocardium. Based on our basic research results, we are developing a multicenter phase II trial on the effects of intramyocardial administration of melatonin-preconditioned BM-MSC in patients with chronic ischemic cardiomyopathy.ConclusionThe ongoing MESAMI program is representative of a translational research program in France

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

Sex differences in wild-type transthyretin amyloidosis: An analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

INTRODUCTION: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is a progressive disease resulting from the accumulation of wild-type transthyretin (TTR) amyloid fibrils, and is diagnosed primarily in males. This analysis examined sex differences in patients with ATTRwt amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS). METHODS: THAOS is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of TTR mutations. THAOS data were analyzed to identify potential differences in demographic and clinical characteristics between males and females with ATTRwt amyloidosis (data cutoff: August 1, 2021). RESULTS: Of 1386 patients with ATTRwt amyloidosis, 84 (6%) were female and 1302 (94%) were male. Females had a higher median age at enrollment (80 vs. 78 years; p = 0.002) and symptom onset (75 vs. 73 years; p = 0.045) than males. Mean left ventricular (LV) ejection fraction was higher (53% vs. 48%; p = 0.001) and mean LV diastolic diameter lower (42 vs. 46 mm; p \u3c 0.001) in females versus males, but sex was not identified as a predictor of LV mean wall thickness adjusted for height (beta coefficient - 0.22; p = 0.460) or a predominantly cardiac phenotype (odds ratio 1.60; p = 0.191). Modified polyneuropathy disability scores differed between groups (p \u3c 0.001), with a larger proportion of scores ≥ IIIa among females (23% vs. 7%). CONCLUSIONS: Females with ATTRwt amyloidosis in THAOS tended to present at a later age and showed signs of less severe cardiac impairment and more severe walking impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745

Early detection and prediction of cardiotoxicity after radiation therapy for breast cancer: the BACCARAT prospective cohort study

International audienceBackground Radiotherapy (RT) for breast cancer presents a benefit in terms of reducing local recurrence and deaths resulting from breast cancer but it can lead to secondary effects due to the presence of neighboring cardiac normal tissues within the irradiation field. Breast RT has been shown to be associated with long-term increased risk of heart failure, coronary artery disease, myocardial infarction and finally cardiovascular death more than 10 years after RT. However, there is still a lack of knowledge for early cardiotoxicity induced by breast RT that can appear long before the onset of clinically significant cardiac events. Based on a 2-year follow-up prospective cohort of patients treated with breast RT, the BACCARAT (BreAst Cancer and CArdiotoxicity Induced by RAdioTherapy) study aims to enhance knowledge on detection and prediction of early subclinical cardiac dysfunction and lesions induced by breast RT and on biological mechanisms potentially involved, based on functional and anatomical cardiac imaging combined with simultaneous assessment of multiple circulating biomarkers and accurate heart dosimetry. Methods/Design BACCARAT study consists in a monocentric prospective cohort study that will finally include 120 women treated with adjuvant 3D CRT for breast cancer, and followed for 2 years after RT. Women aged 50 to 70 years, treated for breast cancer and for whom adjuvant 3D CRT is indicated, without chemotherapy are eligible for the study. Baseline (before RT) and follow-up data include measurements of functional myocardial dysfunction including strain and strain rate based on 2D-speckle tracking echocardiography, anatomical coronary lesions including description of plaques in segments of coronary arteries based on Coronary computed tomography angiography, and a wide panel of circulating biomarkers. The absorbed dose is evaluated for the whole heart and its substructures, in particular the coronary arteries. Analysis on occurrence and evolution of subclinical cardiac lesions and biomarkers will be performed and completed with dose-response relationship. Multivariate model of normal tissue complication probability (NTCP) will also be proposed. Discussion Tools and results developed in the BACCARAT study should allow improving prediction and prevention of potential lesions to cardiac normal tissues surrounding tumors and ultimately enhance patients' care and quality of life. Trial registration ClinicalTrials.gov NCT02605512. © 2016 Jacob et al

Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid

BACKGROUND Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.)