Gene Therapy for Cardiomyopathies

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

La protection du myocarde en chirurgie cardiaque

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

Évaluation de la fonction cardiaque après chirurgie cardiaque au moyen de marqueurs biologiques (intérêt du peptide natriuretique de type B (BNP) et de la troponine I cardiaque)

En réponse à une surcharge hémodynamique de volume ou de pression, le cœur synthétise le peptide natriurétique de type B (BNP). Dans le diagnostique et la surveillance de l'insuffisance cardiaque, le dosage du BNP est actuellement utilisé comme marqueur de la dysfonction ventriculaire. En chirurgie cardiaque, le cœur est soumis à d'importantes modifications de pression et de volume de remplissage. Certaines complications postopératoires se caractérisent par une insuffisance cardiaque de sévérité variable, mais pouvant être lourde de conséquences. Une prise ne charge adaptée et rapide des fonctions cardiaques de ces patients s'impose afin de réduire la morbi-mortalité liée à la défaillance cardiaque post-opératoire. Dans cette étude rétrospective chez les patients ayant eu une intervention chirurgicale cardiaque sous circulation extra-corporelle (CEC), nous avons suivi l'adaptation postopératoire hémodynamique du cœur, en mesurant l'évolution du BNP. De plus, nous avons étudié l'influence de l'ischémie transitoire liée au clampage aortique durant l'intervention par le relargage de troponine I cardiaque dans le sang. Nous montrons qu'après chirurugie cardiaque sous CEC, il existe une sécrétion importante de BNP. Les taux de BNP augmentent selon l'évolution de l'insuffisance cardiaque, néanmoins, cette augmentation n'est pas proportionnelle à l'ischémie préopératoire. Les résultats de cette étude ont montré que le dosage préopératoire du BNP permet d'apporter des informations complémentaires au bilan clinique et échographique préopératoire, et qu'il pourrait servir à identifier de manière objective des patients à risque de complications. Par ailleurs, un dosage juste après l'opération permettrait d'évaluer la tolérance et l'adaptation à des changements hémodynamiques importants, afin d'identifier les patients à risques de complications postopératoires.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Physiopathologie et modifications biochimiques dans la sténose valvulaire aortique

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

Exploring the protective role of GDF5 against skeletal muscle disuse atrophy

International audienceSkeletal muscle is a high plastic tissue able to change its mass upon different stimuli accordingly with environmental changes. Its adaptability depends on many factors and is based on complex mechanisms. Among the process that could alter muscle mass homeostasis, disuse and inactivity induce strong muscle mass and function decrease, having heavy impact on life quality and requiring long time to recover. Growth Differentiation Factor 5 (GDF5) is a crucial player in muscle homeostasis, shown to counteract both denervation- and age-related muscle wasting by limiting the activation of catabolic signals. However, its effects on disuse atrophy following muscle immobilization has to be investigated. In order to establish a potential therapeutic tool having a wide relevance, ranging from disease to microgravity exposure (space flight), we evaluated the consequences of GDF5 overexpression after 10 days of immobilization and 3 weeks of release of hind limb mouse muscles. We observed that local GDF5 overexpression in posterior limbs improved muscle mass loss during immobilization. However, three weeks after release, muscle mass and function were not affected by GDF5 overexpression. We aim to better characterize the effect of GDF5 treatment on several morphological and functional parameters of skeletal muscle upon immobilization/release. In addition, we will assess its eventual benefits at shorter time points after release, in order to establish if GDF5-based treatment could be proposed to shorten the time-window needed for optimal muscle recovery after disuse.In parallel, a study of microgravity exposure was carried on a muscle cell line. We showed that, in the absence of gravity, myotube formation was inhibited, suggesting that this condition could impact cytoskeleton and fusion capability. We will establish if GDF5 treatment might be beneficial for myoblast fusion and myotube morphology during microgravity exposure. In conclusion, our preliminary results suggest that a treatment based on GDF5 could have a therapeutic potential to ameliorate the pathophysiology of muscle during disuse condition to be applied also to space flight and microgravity exposure

The tetrapeptide acetyl-serine-aspartyl-lysine-proline improves skin flap survival and accelerates wound healing

The tetrapeptide acetyl-serine-aspartyl-lysine-proline (AcSDKP) has recently been recognized as a potent angiogenic factor. Given the importance of vascular blood supply in the process of tissue repair we have investigated the ability of AcSDKP to contribute to the repair of cutaneous injuries by using dorsal and abdominal skin flap models. Postoperative subdermal AcSDKP injections (5 mg/ kg/injection twice a day for 3 days following flap elevation) prevented marginally perfused areas from undergoing necrosis. Mean skin survival area of abdominal and dorsal flaps ranged, respectively, from 50.9 19.3 and 53.4 4.2% in the control groups to 66.4 7.5 and 74.7 6.6% in AcSDKP-treated groups. Furthermore, in an ex vivo assay, AcSDKP applied locally to skin explants at doses from 10 8 to 10 5M improved survival of the explanted skin exposed to UVB irradiation at 10 J/cm2. Increased reepithelialization, as well as higher levels of expression of basal keratin 14 and increased expression of fibronectin was observed after topical application of AcSDKP. These data provide experimental evidence that AcSDKP can improve the viability of ischemic skin flaps in the rat by promoting angiogenesis. Moreover, it enhances wound healing of injured avascular skin explants. Thus, these findings identify AcSDKP as a new tissuerepair agent and suggest its potential clinical use for the management of skin wounds

Mutation of δ-Sarcoglycan Is Associated with Ca2+-Dependent Vascular Remodeling in the Syrian Hamster

International audienceWe examined whether mutation of the delta-sarcoglycan gene, which causes dilated cardiomyopathy, also alters the vascular smooth muscle cell (VSMC) phenotype and arterial function in the Syrian hamster CHF 147. Thoracic aorta media thickness showed marked variability in diseased hamsters with zones of atrophy and hypertrophied segments. CHF-147 VSMCs displayed a proliferating/"synthetic" phenotype characterized by the absence of the smooth muscle myosin heavy chain SM2, dystrophin, and Ca(2+)-handling proteins, and the presence of cyclin D1. In freshly isolated VSMCs from CHF 147 hamsters, voltage-independent basal Ca(2+) channels showed enhanced activity similar to that in proliferating wild-type (WT) cells. The transcription factor NFAT (nuclear factor of activated T cells) was spontaneously active in freshly isolated CHF 147 VSMCs, as in proliferating VSMCs from WT hamsters. Mibefradil inhibited B-type channels, NFAT activity, and VSMC proliferation. CHF 147 hamsters had abundant apoptotic cells distributed in patches along the aorta, and clusters of inactive mitochondria were observed in 25% of isolated CHF 147 cells, whereas no such clusters were seen in WT cells. In conclusion, mutation of the delta-sarcoglycan gene increases plasma membrane permeability to Ca(2+), activates the Ca(2+)-regulated transcription factor NFAT, and leads to spontaneous mitochondrial aggregation, causing abnormal VSMC proliferation and apoptosis