Apport de la génomique fonctionnelle en pathologie cardiovasculaire

Les pathologies cardiovasculaires sont un problème majeur de santé publique. Elles sont responsables d'une mortalité élevée. Pour obtenir une meilleure prise en charge de ces affections de nouvelles approches sont nécessaires. La génomique fonctionnelle propose une vision globale du génome et de son expression. Son utilisation dans ẽs pathologies humaines comme les cancers a déjà prouvé tout son intérêt. Ce travail s'attache à montrer comment les études d'expression géhique issues de la génomique fonctionnelle pourront, par l'utilisation de technologies récentes que sont les puces à ADN, apporter de nouvelles données sur ces maladies. Les premiers résultats de ces travaux dans la pathologie cardiovasculaire sont détaillés.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Portraits moléculaires des pathologies cardiaques

Les pathologies cardiaques représentent une cause majeure de morbidité et de mortalité. L'achèvement du séquençage du génome humain a permis le développement de nouvelles approches des maladies comme les études d'expression génique. Au moyen de puces à ADN, les travaux de cette thèse se sont centrés sur l'étude des variations transcriptomales survenant dans l'insuffisance cardiaque et la fibrillation auriculaire chez l'homme. Un profil d'expression génique permettant de prédire le niveau de sévérité clinique des patients en insuffisance cardiaque avancée a été identifié et pourrait servir de base au développement d un biomarqueur du pronostic. Dans la fibrillation auriculaire chronique, l'analyse des variations d expression génique a suggéré l existence d un phénotype tissulaire pro-thrombotique qui pourrait mieux expliquer le risque thromboembolique majeur de la maladie. Ces résultats ont globalement confirmé l'intérêt de l étude des variations transcriptomales dans les maladies cardiaques. La poursuite des travaux déjà engagés devrait non seulement permettre une meilleure compréhension des mécanismes moléculaires des pathologies mais également l'identification de biomarqueurs à but diagnostique, pronostique ou d'orientation thérapeutique.Cardiac diseases remains a major cause of mortality and morbidity. With the completion of the sequencing of the human genome, new techniques like gene expression profiling have been developped to study human diseases. Using DNA-microrrays, we analyzed transcriptomal alterations associated with heart failure and atrial fibrillation in humans. We identified a gene expression profile associated with clinical deterioration of advanced heart failure patients which may be used to better define patients prognosis. Gene expression alteration in chronic atrial fibrillation were suggestive of a hypercoagulable state, a result of potential importance to better understand the pathophysiology of thromboembolic events in atrial fibrillation. Taken together, these results show the great potential of gene expression profiling to study cardiac diseases. Further studies will improve our knowledge of pathological mecanisms occuring in these diseases and will probably provide us with new biomarkers for diagnosis, prognosis and therapy of cardiac diseases.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Duration of sick leave after same-day discharge for lower extremity arterial disease and varicose vein interventions in active population of French patients, 2013–2016: observational study

International audienceObjective To assess whether disparities in rates of same-day discharge for lower extremities arterial disease (5%) and varicose vein interventions (90%) are associated with the burden of postprocedural rehabilitation process, measured through the duration of sick leave.Design Retrospective observational study using French National Health Insurance data in 2012–2016.Setting The French National Health Data System (Système National des Données de Santé), which covers 98.8% of the 66 million people in the French population.Participants French workforce population aged 18 to 65 years old who underwent a first angioplasty with stent placement for lower extremities arterial disease (LEAD, n=30 238) or a first varicose vein intervention (n=265 670) between 2013 and 2016.Main outcome measures Duration and renewals of sick leave within 180 days after endovascular intervention, continuity of care and prescription indices to assess coordination among healthcare professionals after intervention associated with specific intervention settings: conventional (inpatient) or same-day discharge (outpatient). Association was estimated by multivariate negative binomial regressions adjusting for age, gender and comorbidities.Results Outpatient settings decrease the incidence rate ratio (IRR) of the number of cumulated days of sick leave by 14% in both interventions. The increasing variety of prescribers decreases the IRR of cumulated days of sick leave and prescription renewals for varicose interventions by 25% and 21%, respectively, but increases them for LEAD interventions by 240% and 106%. Less coordination between healthcare specialists increases the IRR of cumulative days of sick leave and renewals by 37% and 29% for varicose, and 11% and 9% for LEAD interventions.Conclusions Low rates of outpatients in LEAD angioplasty does not seem related to the duration of sick leave. Outpatient setting reduces the duration of sick leave and their renewals, whatever the intervention. Coordination of healthcare professionals is a key element of interventions follow-up with pathology specificities

Benefits of Performing Same Day Discharge LEAD and Varicose Interventions in Active Patients

International audienceBackground In France, 90% of varicose vein interventions are performed in ambulatory setting while it concerns 7% of angioplasty for lower extremities arterial disease (LEAD). In this study, we made the hypothesis that such disparities may partly be due to the burden of the post-procedural rehabilitation and its relation to patients’ care-pathway and coordination. Methods A retrospective study was conducted on 18 to 65 years old active population who benefited from varicose or LEAD interventions from January 2013 to June 2016 using data from the French National Health Insurance System. Post-procedural rehabilitation measure was the number of cumulated workday break and their renewals within 180 days after intervention. Negative binomial regressions, adjusted for age, gender, and comorbidities, were applied to test associations. The degree of coordination among health care professionals for post-procedural follow-up was tested using the continuity of care and the continuity of prescription indices. Results Compared to inpatient care, day interventions decrease the incidence rate ratio (IRR) of cumulated workday breaks by 14% in both varicose vein and LEAD interventions. The decrease in the degree of coordination between care providers increase the IRR of cumulated workday breaks and renewals by 37% and 29% respectively for varicose, and 11% and 9% for LEAD interventions. The increase in the number of work break prescriptions delivered by the same category of providers decreases the IRR of cumulated workday breaks and their renewals in varicose by 25% and 21% but increases them in LEAD interventions by 240% and 106%. Conclusions Day interventions have similar impacts on rehabilitations after varicose vein and LEAD interventions. However, coordination is critical. Our results highlight the need to pursue health regulatory agencies and healthcare professionals’ works on multidisciplinary ambulatory care networks for better follow-up of acute day care interventions. Key messages Day intervention reduces cumulated workday breaks in endovascular interventions. Multi-specialty coordination of the qualified health care professionals is required in endovascular interventions, especially after angioplasty for LEAD in outpatient settings

Geographical disparities of endovascular revascularisations in ambulatory setting in France from 2015 to 2019

International audienceObjectivesDespite evidences of efficiency and safety ambulatory endovascular revasculatisation for lower extremity arterial disease (LEAD) concerned only 5% of the interventions in France in 2016. Such low rate suggested temporal and geographical space disparities. The aim of this study was to describe the space-time development of ambulatory endovascular revascularisation for LEAD in France and investigates the contributions of health care services and population characteristics as potential determinants.MethodsA retrospective study was conducted on discharge data from French hospitals that performed endovascular procedures for LEAD between 2015 and 2019. Space-time analyses with Moran’s Index, zero-inflated Poisson regression, and clustering approaches were applied. Spatial clusters were compared on the basis of health care services and population characteristics (including poverty and single-man household as proxies of social isolation).ResultsBetween 2015 and 2019, the number of ambulatory interventions has tripled (1104 vs 3130). Out of the 86 French departments, the proportion with > 5% of ambulatory interventions increased from 10.7% to 28.7% over the study period. In 2019, the ambulatory activity in the French departments ranged from 0% to 39%. This evolution was accompanied by a northwest to northeast spatial trend. The clusters of 27 departments with a significant ambulatory activity differed from the others notably by the mortality rate of lower limb arterial thrombo-embolic diseases in male (OR=3.15 95%CI[1.2-8.1]), the proportion of single-man household aged 75 or more (OR=0.37 95%CI [0.2-0.8]), and the poverty rate of people aged 50- to 59-year-old (OR=0.69 95%CI[0.5-0.9]).ConclusionsThe development of ambulatory interventions for LEAD in France is encouraging but heterogeneous. Some determinants of this evolution are clearly population based, with a positive impact of needs to take care of the burden of LEAD but negative effects of social isolation and poverty. Research should be conducted to overcome some patients’ constraints such as isolation

Sex‐Specific Impact of Aldosterone Receptor Antagonism on Ventricular Remodeling and Gene Expression after Myocardial Infarction

Aldosterone receptor antagonism reduces mortality and improves post‐myocardial infarction (Ml) remodeling. Because aldosterone and estrogen signaling pathways interact, we hypothesized that aldosterone blockade is sex‐specific. Therefore, we investigated the mpact of eplerenone on left ventricular (LV) remodeling and gene expression of male infarcted rats versus female infarcted rats. Ml and Sham animals were randomized to receive eplerenone (100 mg/kg/day) or placebo 3 days post‐surgery for 4 weeks and assessed by echocardiography. In the Ml placebo group, left ventricular end‐diastolic dimension (LVEDD) increased from 7.3 ± 0.4 mm to 10.2 ± 1.0 mm ( p < 0.05) and ejection fraction (EF) decreased from 82.3 + 4% to 45.5 + 11% ( p < 0.05) in both sexes ( p = NS between groups). Eplerenone attenuated LVEDD enlargement more effectively in females (8.8 ± 0.2 mm, p < 0.05 vs. placebo) than in males (9.7 ± 0.2 mm, p = NS vs. placebo) and improved EF in females (56.7 ± 3%, p < 0.05 vs. placebo) but not in males (50.6 + 3%, p = NS vs. placebo). Transcriptomic analysis using Rat_230–2.0 microarrays (Affymetrix) revealed that in females 19% of downregu‐lated genes and 44% of upregulated genes post‐MI were restored to normal by eplerenone. In contrast, eplerenone only restored 4% of overexpressed genes in males. Together, these data suggest that aldosterone blockade reduces Ml‐induced cardiac remodeling and phenotypic alterations of gene expression preferentially in females than in males. The use of transcriptomic signatures to detect greater benefit of eplerenone in females has potential implications for personalized medicine

Cardiac nitric oxide synthase-1 localization within the cardiomyocyte is accompanied by the adaptor protein, CAPON

The mechanism(s) regulating nitric oxide synthase-1 (NOS1) localization within the cardiac myocyte in health and disease remains unknown. Here we tested the hypothesis that the PDZ-binding domain interaction between CAPON (carboxy-terminal PDZ ligand of NOS1), a NOS1 adaptor protein and NOS1, contribute to NOS1 localization in specific organelles within cardiomyocytes. Ventricular cardiomyocytes and whole heart homogenates were isolated from sham and post-myocardial infarction (MI) wild-type (C57BL/6) and NOS1 −/− female mice for quantification of CAPON protein expression levels. NOS1, CAPON, xanthine oxidoreductase and Dexras1, a CAPON binding partner, were all present and enriched in isolated cardiac sarcoplasmic reticulum (SR) fractions. CAPON co-immunoprecipitated with the mu and alpha isoforms of NOS1 in whole heart lysates, and co-localization of CAPON and NOS1 was demonstrated in the SR and mitochondria with dual immuno-gold electron microscopy. Following MI, CAPON and NOS1 both redistributed to caveolae and colocalized with caveolin-3. In addition, following MI, expression level of CAPON remained unchanged and Dexras1 was reduced, CAPON binding to xanthine oxidoreductase was augmented and the plasma membrane calcium ATPase (PMCA) increased. In NOS1 deficient myocytes, CAPON abundance in the SR was reduced, and redistribution to caveolae and PMCA binding after MI was absent. Together these findings support the hypothesis that NOS1 redistribution in injured myocardium requires the formation of a complex with the PDZ adaptor protein CAPON

A dynamic, web-accessible resource to process raw microarray scan data into consolidated gene expression values: importance of replication

We propose a freely accessible web-based pipeline, which processes raw microarray scan data to obtain experimentally consolidated gene expression values. The tool MADSCAN, which stands for MicroArray Data Suites of Computed ANalysis, makes a practical choice among the numerous methods available for filtering, normalizing and scaling of raw microarray expression data in a dynamic and automatic way. Different statistical methods have been adapted to extract reliable information from replicate gene spots as well as from replicate microarrays for each biological situation under study. A carefully constructed experimental design thus allows to detect outlying expression values and to identify statistically significant expression values, together with a list of quality controls with proposed threshold values. The integrated processing procedure described here, based on multiple measurements per gene, is decisive for reliably monitoring subtle gene expression changes typical for most biological events