Inhibition of venous bypass graft disease by suppression of deformation induced gene expression of pre-pro-endothelin-1 in vivo – decoy desoxynucleotide vs. Quinapril

Objective: Vein graft disease after aorto-coronary bypass is characterized by massive neointimal and smooth muscle cell proliferation of the vessel presumably due to pressure trauma and endothelin-1 (ET-1) synthesis in the vessel wall. This alteration is induced at the level of transcription of the pre-pro-endothelin-1 (ppET-1) gene. Decoy oligodesoxynucleotide (dODN) and the ACE inhibitor Quinapril (QP) are capable of suppressing deformation-induced gene expression in the vessel wall in vivo.

Material and Methods: In a carotid artery bypass model in rabbits we performed 48 end-to side jugular vein grafts in different treatment groups: (1) 8 grafts were peri-procedually treated with AP-1 consensus dODN, (2) 8 with mutated dODN, (3) 8 with QP, (4) 10 with QP and N(G)-nitro-L-arginine (5) 8 with QP and B (2) receptor antagonist Icatibant, and 6 were untreated controls (6). No anticoagulation was used. Bypass harvest was performed after 28 days. Data were collected by histomorphometric evaluation and statistical analysis with Kruskal-Wallis-Test and post hoc Mann-Whitney U-Test.

Results: Intimal thickness of treatment groups (median): (1) 28.3mm, (2) 48.4mm, (3) 91.8mm, (4) 60.5mm, (5) 164.3mm, (6) 71.1mm. All groups were of final equal size (QP: n=5). 25 animals had to be excluded due to bypass thrombosis. DODN treatment resulted in a significant reduction of neointimal formation (p=0.029) vs. control and (p=0.016) vs. Quinapril treatment.

Conclusions: Results indicate that in this model neointimal proliferation could be reduced with consensus dODN. Quinapril was not equal efficient. The results encourage the use of dODN in coronary artery surgery for prevention of venous graft disease.