Impact du polymorphisme du cytochrome P450 2C19 chez de jeunes coronariens traités par Clopidogrel au décours d un syndrome coronaire aigu

La survenue de syndromes coronaires aigus (SCA) est peu fréquente chez les patients de moins de 45 ans. La maladie coronaire du sujet jeune constitue un modèle physiopathologique de thrombose où les facteurs de risque traditionnels d athérosclérose sont rares . Par ailleurs ces jeunes patients ont une espérance de vie longue, et sont plus particulièrement exposés à des récidives d évènements cardio-vasculaires. L obtention d un traitement anti-thrombotique optimal est donc indispensable pour cette population. L efficacité des traitements antiagrégants plaquettaires (aspirine et thiénopyridine - dont le clopidogrel) pour prévenir les complications thrombotiques artérielles liées à l athérosclérose est bien établie. Cependant, il existe une grande variabilité inter-individuelle de la réponse plaquettaire au clopidogrel aux posologies recommandées, avec une proportion non négligeable de patients mauvais répondeurs , faisant naître le concept de résistance au clopidogrel. Cette résistance biologique au clopidogrel est associée à une réduction de l efficacité thérapeutique en terme de prévention des accidents thrombotiques. L étude de la pharmacogénétique du clopidogrel a permis de démontrer clairement que le polymorphisme du cytochrome P450 2C19 jouait un rôle dans la variabilité de réponse au clopidogrel, notamment chez les patients à haut risque cardiovasculaire, sans que son impact direct sur les évènements cliniques n ait pu être démontré. Dans le cadre d une étude sur 259 jeunes coronariens bénéficiant d un traitement chronique par clopidogrel au décours d un syndrome coronaire aigu, nous avons pu déterminer que la présence du variant allélique CYP 2C19 *2 était associée à un rapport de risque élevé de présenter une récidive d évènement ischémique. Ce variant allélique est fréquent avec une prévalence de 14 à 18% dans la population. Ces résultats suggèrent l intérêt de rechercher la présence du variant 2C19 *2 chez les patients coronariens dans le cadre de l évaluation globale de leur risque cardiovasculaire, et afin de dépister ceux à risque de présenter une récidive d événement clinique. L augmentation de posologie de la dose d entretien du clopidogrel, ou le remplacement du clopidogrel par une autre thiénopyridine, le prasugrel, ne semblant pas présenter de variabilité de réponse, seraient alors deux propositions thérapeutiques intéressantes, en cours d évaluation, mais non encore validées.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Prevalence of tubulopathy and association with renal function loss in HIV-infected patients

International audienceBackground: The incidence of chronic kidney disease (CKD) is 10 times higher in human immunodeficiency virus (HIV)-infected patients than in the general population. We explored the prevalence and determinants of proximal tubular dysfunction (PTD) in HIV-infected individuals, and assessed the impact of the tubulopathy on the estimated glomerular filtration rate (eGFR) outcome.Methods: A cohort study was performed on 694 outpatients followed in a French centre to analyse the prevalence of PTD, the diagnosis performance of screening tools and the associated factors. eGFR was prospectively evaluated to analyse the predictive value of the tubulopathy on eGFR decrease.Results: At inclusion, 14% of the patients presented with PTD and 5% with CKD. No individual tubular marker, including non-glomerular proteinuria, glycosuria dipstick or hypophosphataemia, registered sufficient performance to identify PTD. We found a significant interaction between tenofovir disoproxil fumarate exposure and ethnicity (P = 0.03) for tubulopathy risk. Tenofovir disoproxil fumarate exposure was associated with PTD in non-Africans [adjusted odds ratio (aOR) = 4.71, P < 10-3], but not in patients of sub-Saharan African origin (aOR = 1.17, P = 0.73). Among the 601 patients followed during a median of 4.3 years, 13% experienced an accelerated eGFR decline. Unlike microalbuminuria and glomerular proteinuria, tubulopathy was not associated with accelerated eGFR decline.Conclusion: PTD is not rare in HIV-infected individuals but is less frequent in sub-Saharan African patients and is associated with tenofovir disoproxil fumarate exposure only in non-Africans. Its diagnosis requires multiple biochemical testing and it is not associated with an accelerated eGFR decline

P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction

International audiencePRIVATE-ATLANTIC (P2Y12 Receptor Inhibition with VASP Testing using Elisa kit during the ATLANTIC study) is a pre-specified substudy of the randomised, double-blind ATLANTIC trial in patients with ST-segment elevation myocardial infarction, designed to help interpret the main trial results. The primary objective of ATLANTIC was to assess coronary reperfusion prior to percutaneous coronary intervention (PCI) with pre- vs in-hospital ticagrelor 180 mg loading dose (LD). PRIVATE-ATLANTIC assessed platelet inhibition in 37 patients by measurement of vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and VerifyNow platelet reactivity units (PRU) before angiogram (T1), immediately after PCI (T2), 1 (T3), and 6 (T4) hours (h) after PCI, and before next study drug administration (T5). The median time difference between the two ticagrelor LD was 41 minutes. Platelet reactivity was unaffected at T1 when measured by VASP-PRI (89.8 vs 93.9 % for pre- and in-hospital ticagrelor, respectively; p = 0.18) or PRU (239 vs 241; p = 0.82). Numerical differences were apparent at T2 and maximal at T3. Morphine administration significantly delayed onset of platelet inhibition at T3 (VASP-PRI 78.2 vs 23.4 % without morphine; p = 0.0116) and T4 (33.1 vs 11.0 %; p = 0.0057). In conclusion, platelet inhibition in ATLANTIC was unaffected by pre-hospital ticagrelor administration at the time of initial angiogram due to the short transfer delay. The maximum difference in platelet inhibition was detected 1 h after PCI (T3). Morphine administration was associated with delayed onset of action of ticagrelor and appeared more important than timing of ticagrelor administration.TRIAL REGISTRATION:ClinicalTrials.gov NCT01347580

Long-Term Evolution of Premature Coronary Artery Disease

International audienceBACKGROUND:The long-term evolution of premature coronary artery disease (CAD) is unknown.OBJECTIVES:The objective of this study was to describe the evolution of coronary atherosclerosis in young patients and identify the risk factors of poor outcomes.METHODS:Participants age ≤45 years with acute or stable obstructive CAD were prospectively enrolled and followed. The primary endpoint was all-cause death, myocardial infarction (MI), refractory angina requiring coronary revascularization, and ischemic stroke.RESULTS:Eight hundred-eighty patients with premature CAD were included. They were age 40.1 ± 5.7 years, mainly men, smokers, with a family history of CAD or hypercholesterolemia. At baseline presentation, 91.2% underwent coronary revascularization, predominantly for acute MI (78.8%). Over a follow-up of 20 years, one-third (n = 264) of patients presented with a total of 399 ischemic events, and 36% had at least a second recurrent event. MI was the most frequent first recurrent event (n = 131 of 264), mostly related to new coronary lesions (17.3% vs. 7.8%; p = 0.01; hazard ratio [HR]:1.45; 95% confidence interval [CI]: 1.09 to 1.93 for new vs. initial culprit lesion). All-cause death (n = 55; 6.3%) occurred at 8.4 years (median time). Ethnic origin (sub-Saharan African vs. Caucasian, adjusted hazard ratio [adjHR]: 1.95; 95% CI: 1.13 to 3.35; p = 0.02), inflammatory disease (adjHR: 1.58; 95% CI: 1.05 to 2.36; p = 0.03), and persistent smoking (adjHR: 2.32; 95% CI: 1.63 to 3.28; p < 0.01) were the strongest correlates of a first recurrent event. When considering all recurrent events, the same factors and Asian ethnicity predicted poor outcome, but persistent smoking had the greatest impact on prognosis.CONCLUSIONS:Premature CAD is an aggressive disease despite the currently recommended prevention measures, with high rates of recurrent events and mortality. Ethnicity and concomitant inflammatory disease are associated with poor prognoses, along with insufficient control of risk factors

Autochthonous dengue outbreak in Nîmes, South of France, July to September 2015

International audienceIn August and September 2015, seven locally acquired cases of dengue virus type 1 (DENV-1) were detected in Nîmes, south of France, where Aedes albopictus has been established since 2011. Epidemiological and entomological investigations allowed to steer vector control measures to contain transmission. An imported case from French Polynesia with onset fever on 4 July was identified as primary case. This outbreak occurred from 8 August to 11 September in a 300m radius area. Six sprayings to control mosquitos were performed in the affected area. We describe the first considerable dengue outbreak in mainland France where only sporadic cases of autochthonous dengue were recorded previously (2010, 2013 and 2014). The 69 day-period between the primary case and the last autochthonous case suggests multiple episodes of mosquito infections. The absence of notification of autochthonous cases during the month following the primary case’s symptoms onset could be explained by the occurrenceof inapparent illness. Recurrence of cases every year since 2013, the size of the 2015 outbreak and continuing expansion of areas with presence of Ae. albopictus highlight the threat of arboviral diseases in parts of Europe. Thus, European guidelines should be assessed and adjusted to the current conte

Loss-of-Function Mutations inUNC45ACause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function