Fluvastatin in combination with rad significantly reduces graft vascular disease in rat cardiac allografts

Background. RAD is a potent immunosuppressive agent that has been shown to be effective in preventing acute and chronic allograft rejection in animal models. The HMGCoA reductase inhibitors have been found to reduce the incid ence of graft vascular disease (GVD) in heart transplant patients and in an imal mo els. This study was designed to investigate the effects of fluvasta tin or pravastatin in a rodent model of GVD produced using low doses of RAD to prevent acute rejection. Methods. Hearts from Fisher 344 rats were heterotopically transplanted to L ewis rat recipients. RAD was administered orally at 0.5 mg/kg per day for d ays 0 to 14 and then 0.25 mg/kg per day for an additional 85 days to preven t acute rejection but allow for the development of GVD. Pravastatin (20 mg/ kg per day) or fluvastatin (2 or 6 mg/kg per day) was added to the RAD trea tment. At the end of a 100-day treatment period, the hearts were harvested for morphometric and histopathologic examinations. Results. Rats treated with fluvastatin, at either dose, had a significant ( P less than or equal to0.0239) decrease in coronary arterial intimal thicke ning (GVD) of approximately 43%. Rats treated with pravastatin had a 22% re duction in GVD that did not reach statistical significance. Treatment with fluvastatin, but not pravastatin, decreased the degree of endomyocardial mo nonuclear cell infiltration seen with RAD administered alone. Conclusions. Fluvastatin significantly decreased GVD in a rat model produce d using low-dose RAD immunosuppression. To a lesser extent, pravastatin als o decreased GVD in this model. These data lend further support for the stud y of fluvastatin, pravastatin, and other HMG-CoA reductase inhibitors for t he prevention of GVD in cardiac transplant patients.