Related Experiment Videos
Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients
H Hölschermann1, A Hilgendorff, B Kemkes-Matthes
1Department of Internal Medicine, Justus-Liebig-University Giessen, Germany. hans.f.hoelschermann@innere.med.uni-giessen.de
Insights
Low-dose simvastatin reduces monocyte tissue factor (TF) expression and hypercoagulability in heart transplant recipients. This may help prevent transplant coronary artery disease by inhibiting TF gene transcription.
Area of Science:
- Cardiology
- Immunology
- Pharmacology
Background:
- Statins (HMG-CoA reductase inhibitors) reduce cardiac allograft failure and transplant coronary artery disease via unknown mechanisms.
- Low-dose simvastatin inhibits monocyte tissue factor (TF) and reduces hypercoagulability in heart transplant recipients.
Purpose of the Study:
- To investigate the effect of simvastatin on monocyte tissue factor (TF) expression and coagulation activation in cardiac transplant recipients.
Main Methods:
- Fifteen heart transplant recipients received 10 mg daily simvastatin.
- Monocyte TF activity was measured using a one-stage clotting assay before and during simvastatin therapy.
- TF gene transcription was assessed by reverse transcriptase-polymerase chain reaction.
Main Results:
- Cardiac transplant recipients showed increased monocyte TF activity compared to controls.
- Simvastatin significantly reduced monocyte TF activity, independent of lipid lowering.
- TF reduction was linked to inhibited TF gene transcription and normalization of coagulation markers.
Conclusions:
- Simvastatin's inhibition of monocyte TF expression and attenuation of hypercoagulability may protect against transplant coronary artery disease.
- This mechanism offers a potential explanation for statin's benefits in cardiac transplant recipients.
Background:
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors 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 here report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulability 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 therapy. Levels of TF activity in both unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells drawn from transplant recipients before and under simvastatin therapy were evaluated by one-stage clotting assay.
Results:
Monocyte TF activity was found to be significantly increased in cardiac 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 reduction of serum low-density lipoprotein cholesterol. As demonstrated by reverse transcriptase-polymerase chain reaction, monocyte TF reduction by simvastatin, observed in 13 of the 15 transplant recipients investigated, could be ascribed to an inhibition of monocyte TF gene transcription. The reduction of monocyte TF activity during treatment with simvastatin paralleled with the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and fibrin formation indicating coagulation activation after cardiac transplantation.
Conclusion:
Inhibition of monocyte TF expression and attenuation of the persistent hypercoagulable state observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of transplant coronary artery disease.