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Chapter 8: CARDIOVASCULAR TISSUE MODIFICATION BY GENETIC APPROACHES MYOCARDIAL GENE TRANSFER

Direct injection of DNA into myocardial tissue has been shown to be effective in local delivery of a transgene to the heart. Lin et al.37 reported in vivo expression of f-'-galactosidase in cardiac myocytes for at least 4 weeks after direct injection into the left ventricle. Direct injections of a major histocompatibility complex (MHC) gene and the reporter gene luciferase under the control of an MHC promoter also resulted in the regulated expression of these genes.38 Subsequent studies also showed increased gene expression after myocardial injection of adenoviral vectors.10-13

Healing and remodeling of the ventricle after myocardial infarction remain as important clinical problems. Some candidate genes (e.g., those for TGF-ftl and myogenin) may enhance the healing and recovery of myocytes after injury associated with infarction. The induction of neovascularization or angiogenesis in ischemic myocardium after coronary artery occlusion using gene transfer may salvage myocardium at risk by enhancing blood supply to the ischemic areas. Indeed, intracardiac myoblast grafts stably transfected with an inducible TGF-ftl construct were associated with increased DNA synthesis in vascular endothelial cells, consistent with a sustained angiogenic response.86 The success of intracardiac grafting with genetically modified cardiomyocytes depends on the ability of grafts to couple with host myocytes. Soonpaa et al.87 demonstrated that fetal cardiomyocytes isolated from transgenic mice carrying a fusion protein of the cardiac d-MHC promoter with a P-galactosidase reporter gene were connected to the host myocardium by nascent intercalated disks formed after grafting. Chronic heart failure is accompanied by a reduction in the number of myocardial ^-adrenergic receptors and inotropic responsiveness. Cardiac-specific overexpression of a ^-adrenergic receptor in a transgenic animal model with subsequent increased myocardial function suggests a potential gene-therapy approach to heart failure.88

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