An estimated four million people suffer from congestive heart disease in the United States. The annual death rate from this condition is about half a million and the reduction of these numbers is dependent on heart transplant surgery. However the availability of donor hearts is severely limited (+/- 2000/annum) and is unlikely to improve. Patients awaiting transplantation may resort to implantation of a left ventricular assist device (LVAD) since this, not only retards further general, deterioration, but improves cardiovascular performance. This procedure, which was primarily developed as a """"""""bridging"""""""" strategy for transplant patients awaiting donor hearts, may become an alternative to new heart transplantation. The performance of LVADs has been marred by episodes of thrombosis, these occur both soon after implantation (within first 48 hr) and at later stages (after 20-30 days), initiation of the latter appears random and unpredictable. In an effort to prevent these life-threatening events we propose to cover the blood-contacting LVAD surfaces with cells genetically engineered to produce prostacyclin and endothelium-derived relaxing factor, identified as NO, two compounds that inhibit platelet aggregation. The enhanced production of prostacyclin will be engineered into autologous saphenous vein endothelial and smooth muscle cells by viral-vector introduction of prostaglandin H synthase (PGHS). NO production will be accomplished by introduction of NO synthase genes into smooth muscle cells. Since high yields of autologous endothelial cells are difficult to obtain, these will be used to cover the Dacron inlet surfaces at the pump-tissue interface. These are the sites of early thrombosis whereas the textured pump surfaces, that become rapidly covered with a fibrin coagulum following implantation, maybe more involved in the initiation of later thromboembolic events. Production of NO by smooth muscle cells covering the textured pump surfaces will prevent both platelet activation (in combination with prostacyclin) and excessive smooth muscle cell proliferation. Activity of NO synthase (NOS), the enzyme responsible for NO production is dependent on a cofactor, tetrahydrobiopterin. De novo synthesis of this factor is regulated GTP cyclohydrolase activity. Introduction of GTP cyclohydrolase genes into smooth muscle cells will ensure full productivity of NOS. The modification of smooth muscle cells to produce prostacyclin and NO constitutively will engender them with anti-coagulant properties that are normally associated with the endothelium and yet their proliferative activity, an apparent disadvantage to the use of myocytes, will be controlled by the production of NO.
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