Abstract 11891: Chronic Allograft Vasculopathy is Promoted by Increased Mitochondrial Activity
Background: This study aimed at investigating the efficacy of dichloracetate (DCA) to prevent the development and progression of chronic allograft vasculopathy (CAV) by regulating the mitochondrial metabolism of aberrant proliferating smooth muscle cells (SMCs).
Methods: Orthotopic aortic transplantations (n=42) were performed in the chronic PVG-to-ACI rat model. Immunosuppression with DCA (0.75mg/L) or everolimus/clopidogrel (4 mg/kg and 1mg/kg per os, respectively) was either started early (day 0 to 120) or delayed when CAV was already present (day 80 to 120). Blood analysis was used for side effect screening. Aortic luminal obliteration was quantified using computer morphometry. Confocal immunofluorescence microscopy was used to identify aberrant proliferating SMCs. In vitro proliferation and scratch assays were performed to investigate the direct effect of used drugs on PDGF stimulated SMCs.
Results: Untreated animals developed CAV with luminal obliteration of 40.1±24.2% after 120 days. Continuous immunosuppression with DCA or everolimus/clopidogrel effectively prevented the development of vasculopathy (7.9±4 and 8.1±12.9, respectively; p<0.001 vs. no treatment). When the start of the immunosuppressive regimen was delayed until postoperative day 80, DCA and everolimus/clopidogrel inhibited a progression of established CAV (6.6±8 and 5.3±4.6; p<0.001 vs. no treatment). Even more importantly, both treatment regimens did also reverse the luminal obliteration (p<0.001). Interestingly, delayed treatment of DCA induced apoptosis resulting in shrinking hyperplasia area and inhibition of aberrant SMC proliferation. DCA was very well tolerated without showing any side effects. In vitro assays revealed a significant inhibition of SMC proliferation/migration by everolimus/clopidogrel and DCA (p<0.001 vs. control)
Conclusions: DCA prevents the development of CAV and not only inhibits a progression of established disease, but also reverses the established disease by inducing apoptosis. It shows a similar efficacy but a safer drug profile when compared to everolimus/clopidogrel, since only aberrant SMC seem to be affected.
- © 2012 by American Heart Association, Inc.