at preservation of the function in a chronically failing heart. Plasmid. IGF-I was delivered to the cardiac muscle by direct intracardiac injection. Multiple injections ...
CARDIAC GENE AND CELL THERAPY inexpensiveness, ease in handling, but the major disadvantage is that the transfection efficiency has been relatively poor. However, in the context of a secreted protein, this technical hurdle might be less prominent than when concerning a structural protein. We assessed the in vivo expression of naked plasmid DNA aiming at preservation of the function in a chronically failing heart. Plasmid IGF-I was delivered to the cardiac muscle by direct intracardiac injection. Multiple injections are needed in order to obtain sufficient in vivo modulation of the cardiac function. No severe side effects directly related to multiple injections were observed. Furthermore, high doses of plasmid DNA had to be injected locally, but no adverse reaction due to the amount of DNA was observed at the sites of injection. Protein expression was assessed by immunohistochemistry. IGF-1 treatment appeared to induce cardiac preservation in the cardiomyopathic hamster model, as cardiac muscle mass remained unchanged; we observed a lesser dilatation of the cardiac cavities and greater wall thickness. Moreover, vehicle-treated hamsters exhibited significant decrease in left ventricular functional parameters. At steady state, in plasmid-treated animals, cardiac output raised, mainly due to increased stroke volume, when heart rate remained unchanged. The left ventricular (LV) dP/dt(max) was enhanced by IGF-1, which reflected increased contractility, as the LV filling pressure decreased. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by IGF-1. Enhancing cellular function in cardiomyopathic hamster hearts appears to have beneficial effects on global cardiac function. These studies show that plasmid IGF-I delivery may improve cardiac function and such a strategy might be used for otherwise untreatable patients. The aim is to preserve the ventricular contractile mass by stimulating the hypertrophic pathway and hereby to rescue cardiac function.
925. Electroporation Mediated Gene Transfer of Human Interleukin-10 to Skeletal Muscle Reduces Acute Rejection in Rat Cardiac Allografts Reza Tavakoli,2 Amiq Gazdhar,1 Jaroslaw Pierog,1 Anna Bagdannova,3 Mathias Gugger,4 Steven Hyde,5 Michele Genoni,2 Ralph Schmid.1 1 Division of General Thoracic Surgery, University Hospital, Bern, BE, Switzerland; 2Division of Cardiac Surgery, Trimeli Hospital, Zurich, ZH, Switzerland; 3Institute of Veterinary Physiology, University of Zurich, Zurich, ZH, Switzerland; 4Institute of Pathology, University of Bern, Bern, BE, Switzerland; 5Nuffield Department of Clinical Laboratory Science, John Radcliff Hospital, University of Oxford, Oxford, OX, United Kingdom. Background Electroporation-mediated transfer of plasmid DNA has been demonstrated to enhance gene transduction dramatically. The aim of this study was to investigate the impact of overexpression of human IL-10 (hIL-10) on acute rejection of cardiac allografts in the rat. Methods Heterotopic heart allotransplantation was performed in 12 animals (Brown Norway to Fischer F344) divided in two groups. Plasmid DNA (PCIKhIL10) was injected IM into the tibialis anterior muscle of the recipient followed by electroporation (4x10ms pulses at 200V/cm), 24h prior to the transplantation. In group A (n=6) 2.5 µg of pCIK hIL10 and in group B (n=6) distilled water was injected. Graft function was assessed by daily palpation. At day 7 animals were sacrificed and pripheral blood was drawn for ELISA measurement of hIL-10. Tissue samples were preserved for myeloperoxidase measurement and histology. Results In all animals in group A heart allografts were still beating at day 7 whereas they stopped beating at day 5±1 in group B (p
