138 research outputs found

    Gene Therapy for Cardiomyopathies

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    Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Molecular genetics was integrated quite late in cardiology, but introduced new concepts like sarcolemmopathies, cytoskeletalopathies, and channelopathies useful to better understand the pathophysiology of the development of inherited cardiomyopathies (CMs). As our understanding of the cellular and molecular processes involved in the development and progression of heart disease improved, new therapeutic targets were identified, as were novel approaches such as delivery of genes to replace defective or deficient components and thereby restore structure or function in a diseased heart. We discuss gene addition strategies in the context of monogenic disorders. Moreover, a broader nucleic acid-based modulation of cardiac gene expression for the treatment of cardiac diseases might have larger clinical indications. Inadequate gene delivery remains a potential cause of negative trials. However, progress in innovative formulations and clinically relevant ways of administration should lead to significant progress in the future. Cardiac gene therapy will be integrated into the therapeutic armamentarium for CM and heart failure

    N011 Culture et délivrance au niveau du tissu cardiaque de cardiomyocytes issus de cellules souches embryonnaires humaines au moyen de matrices tridimensionelles poreuses à base de polysaccharides

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    Un intĂ©rĂȘt particulier a Ă©tĂ© portĂ© ces derniĂšres annĂ©es Ă  la thĂ©rapie cellulaire rĂ©paratrice cardiaque. Les cellules souches embryonnaires humaines (hES) sont une source prouvĂ©e de cardiomyocytes et les premiĂšres donnĂ©es in vivo suggĂšrent leurs capacitĂ©s fonctionnelles Ă  type d’effet pacemaker ou rĂ©paratrices d’infarctus du myocarde. Nous avons Ă©tudiĂ© un mode de dĂ©livrance des cellules hES dans le tissu cardiaque basĂ© sur une matrice 3D servant de support Ă  la fois pour la culture des cellules et pour leur implantation au contact du myocarde.Des matrices poreuses de polysaccharides (pullulane et dextrane) ont Ă©tĂ© prĂ©parĂ©es par rĂ©ticulation chimique permettant de rĂ©aliser des films avec des pores de 100 Ă  200 microns. Les matrices ont Ă©tĂ© recouvertes de diffĂ©rentes protĂ©ines; les cellules hES indiffĂ©renciĂ©es ont Ă©tĂ© cultivĂ©es sur fibroblastes murins, en milieu supplĂ©mentĂ© avec du sĂ©rum knock-out et du FGF2. Dans une premiĂšre partie in vitro, nous avons mis en Ă©vidence par q-RT-PCR, observation microscopique et imagerie confocale, la diffĂ©renciation en cardiomyocytes de cellules hES directement cultivĂ©es dans les matrices en prĂ©sence d’un milieu inducteur de diffĂ©rentiation; les matrices permettaient aussi la culture, l’expansion et la survie Ă  long terme de parties battantes obtenues Ă  partir de corps embryoĂŻdes issus d’hES et isolĂ©es manuellement. Nous avons ensuite Ă©tudiĂ© le devenir des cellules hES dans un modĂšle de lĂ©sions cardiaques par dĂ©pĂŽt de films poreux cellularisĂ©s sur les cƓurs infarcis de souris NOD SCID. L’identification est confirmĂ©e pour les cardiomyocytes issus d’ES d’une lignĂ©e de cellules hES H9 GFP+ ainsi que d’une lignĂ©e de cellules hES dans laquelle l’expression de la GFP est sous contrĂŽle d’un promoteur spĂ©cifique du tissu cardiaque, Nkx2.5. Nous avons ainsi mis en Ă©vidence la migration des cellules ES Ă  diffĂ©rents stades de diffĂ©renciation Ă  partir des matrices 3D vers les souris NOD SCID ainsi que leur diffĂ©renciation en cardiomyocytes. Les donnĂ©es de PCR quantitative sur la base du transgĂšne GFP mettent en Ă©vidence une meilleure survie des ES dĂ©livrĂ©es par l’intermĂ©diaire des matrices 3D en comparaison avec une administration directe. Une Ă©tude fonctionnelle comparative est en cours

    Effects of Vagus Nerve Stimulation on Sleep-related Breathing in Epilepsy Patients

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    Purpose: To describe the effects of vagus nerve stimulation (VNS) on sleep-related breathing in a sample of 16 epilepsy patients. Methods: Sixteen adults with medically refractory epilepsy (nine men, seven women, ages 21–58 years) underwent baseline polysomnograms (PSGs). Three months after VNS therapy was initiated, PSGs were repeated. In addition, patient 7 had a study with esophageal pressure monitoring, and patient 1 had a continuous positive airway pressure (CPAP) trial. Results: Baseline PSGs: One of 16 patients had an apnea–hypopnea index (AHI) >5 (6.8). Treatment PSGs: Five of 16 patients had treatment AHIs >5. Respiratory events were more frequent during periods with VNS activation (on-time) than without VNS activation (off-time; p = 0.016 ). Follow-up studies: Esophageal pressure monitoring in patient 7 showed crescendos in esophageal pressure during VNS activation, supporting an obstructive pattern. The CPAP trial of patient 1 showed that all respiratory events were associated with VNS stimulation at low CPAP levels. They were resolved at higher CPAP levels. Conclusions: Treatment with VNS affects respiration during sleep and should be used with care, particularly in patients with preexisting obstructive sleep apnea. The AHI after VNS treatment remained <5 in the majority of patients and was only mildly elevated (<12) in five patients. In one patient, CPAP resolved VNS-related respiratory events.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66447/1/j.1528-1157.2003.56202.x.pd

    Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype

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    Objective: Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in NEFH have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC). Methods: In this large observational study, we present phenotype–genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families. Results: The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients. All families harboured heterozygous frameshift variants in the last exon of NEFH, resulting in a reading frameshift to an alternate open reading frame and the translation of approximately 42 additional amino acids from the 3' untranslated region (3â€Č-UTR). Conclusions: This phenotype–genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in NEFH variant interpretation in the context of the disease’s unique molecular genetics

    Coronary artery surgery: cardiotomy suction or cell salvage?

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    Coronary artery bypass grafting (CABG) today results in what may be regarded as acceptable levels of blood loss with many institutions avoiding allogeneic red cell transfusion in over 60% of their patients. The majority of cardiac surgeons employ cardiotomy suction to preserve autologous blood during on-pump coronary artery bypass surgery; however the use of cardiotomy suction is associated with a more pronounced systemic inflammatory response and a resulting coagulopathy as well as exacerbating the microembolic load. This leads to a tendency to increased blood loss, transfusion requirement and organ dysfunction. Conversely, the avoidance of cardiotomy suction in coronary artery bypass surgery is not associated with an increased transfusion requirement. There is therefore no indication for the routine use of cardiotomy suction in on-pump coronary artery surgery

    Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors

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    Blockade of the renin-angiotensin system (RAS) is well recognized as an essential therapy in hypertensive, heart, and kidney diseases. There are several classes of drugs that block the RAS; these drugs are known to exhibit antifibrotic action. An analysis of the molecular mechanisms of action for these drugs can reveal potential differences in their antifibrotic roles. In this review, we discuss the antifibrotic action of RAS blockade with an emphasis on the potential importance of angiotensin I-converting enzyme (ACE) inhibition associated with the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP)

    La protection du myocarde en chirurgie cardiaque

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    CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

    Évaluation de la fonction cardiaque aprĂšs chirurgie cardiaque au moyen de marqueurs biologiques (intĂ©rĂȘt du peptide natriuretique de type B (BNP) et de la troponine I cardiaque)

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    En rĂ©ponse Ă  une surcharge hĂ©modynamique de volume ou de pression, le cƓur synthĂ©tise le peptide natriurĂ©tique de type B (BNP). Dans le diagnostique et la surveillance de l'insuffisance cardiaque, le dosage du BNP est actuellement utilisĂ© comme marqueur de la dysfonction ventriculaire. En chirurgie cardiaque, le cƓur est soumis Ă  d'importantes modifications de pression et de volume de remplissage. Certaines complications postopĂ©ratoires se caractĂ©risent par une insuffisance cardiaque de sĂ©vĂ©ritĂ© variable, mais pouvant ĂȘtre lourde de consĂ©quences. Une prise ne charge adaptĂ©e et rapide des fonctions cardiaques de ces patients s'impose afin de rĂ©duire la morbi-mortalitĂ© liĂ©e Ă  la dĂ©faillance cardiaque post-opĂ©ratoire. Dans cette Ă©tude rĂ©trospective chez les patients ayant eu une intervention chirurgicale cardiaque sous circulation extra-corporelle (CEC), nous avons suivi l'adaptation postopĂ©ratoire hĂ©modynamique du cƓur, en mesurant l'Ă©volution du BNP. De plus, nous avons Ă©tudiĂ© l'influence de l'ischĂ©mie transitoire liĂ©e au clampage aortique durant l'intervention par le relargage de troponine I cardiaque dans le sang. Nous montrons qu'aprĂšs chirurugie cardiaque sous CEC, il existe une sĂ©crĂ©tion importante de BNP. Les taux de BNP augmentent selon l'Ă©volution de l'insuffisance cardiaque, nĂ©anmoins, cette augmentation n'est pas proportionnelle Ă  l'ischĂ©mie prĂ©opĂ©ratoire. Les rĂ©sultats de cette Ă©tude ont montrĂ© que le dosage prĂ©opĂ©ratoire du BNP permet d'apporter des informations complĂ©mentaires au bilan clinique et Ă©chographique prĂ©opĂ©ratoire, et qu'il pourrait servir Ă  identifier de maniĂšre objective des patients Ă  risque de complications. Par ailleurs, un dosage juste aprĂšs l'opĂ©ration permettrait d'Ă©valuer la tolĂ©rance et l'adaptation Ă  des changements hĂ©modynamiques importants, afin d'identifier les patients Ă  risques de complications postopĂ©ratoires.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF
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