Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients

Background, 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhib itors have been shown to reduce cardiac allograft failure and to lower the incidence of transplant coronary artery disease, These effects result from as yet unknown mechanisms not clearly attributable to lipid lowering. We he re report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulabili ty state seen in cardiac transplant recipients. Methods, Fifteen consecutive heart transplant recipients receiving standard oral immunosuppression were newly assigned to a 10 mg daily simvastatin th erapy. Levels of TF activity in both unstimulated and lipopolysaccharide-st imulated peripheral blood mononuclear cells drawn from transplant recipient s before and under simvastatin therapy were evaluated by one-stage clotting assay. Results. Monocyte TF activity was found to be significantly increased in ca rdiac transplant recipients when compared with healthy controls. Excessive monocyte procoagulant activity was reduced in cardiac transplant recipients during simvastatin treatment. This effect occurred independently of the re duction of serum low-density lipoprotein cholesterol. As demonstrated by re verse transcriptase-polymerase chain reaction, monocyte TF reduction by sim vastatin, observed in 13 of the 15 transplant recipients investigated, coul d be ascribed to an inhibition of monocyte TF gene transcription. The reduc tion of monocyte TF activity during treatment with simvastatin paralleled w ith the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and f ibrin formation indicating coagulation activation after cardiac transplanta tion. Conclusion, Inhibition of monocyte TF expression and attenuation of the per sistent hypercoagulable state observed in cardiac transplant recipients dur ing treatment with simvastatin may represent an important mechanism by whic h HMG-CoA reductase inhibitors protect against the development of transplan t coronary artery disease.