Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia.
OBJECTIVE
More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is an initial, critical step in the progression toward occlusion. To date, no clinically relevant large animal models of aortocoronary saphenous vein graft intimal hyperplasia have been fully characterized. Gene therapy holds promise as a novel treatment for aortocoronary saphenous vein graft intimal hyperplasia. The 2 objectives of this study are to characterize a canine model of aortocoronary saphenous vein graft intimal hyperplasia and to demonstrate that ex vivo gene delivery is possible in these grafts using adenoviral vectors.


METHODS
Ten dogs underwent aortocoronary bypass grafting using saphenous veins. Six dogs underwent serial arteriograms to monitor graft patency. On postoperative day 90, the dogs were killed and their grafted and nongrafted saphenous veins were studied histologically. Four dogs underwent the same procedure, but their saphenous veins were treated with 1 x 10(12) total viral particles of a replication-deficient, recombinant adenovirus containing beta-galactosidase (n = 2) or the beta-adrenergic receptor kinase carboxyl terminus (n = 2). These animals were killed on postoperative day 7 for determination of transgene expression.


RESULTS
All grafts were demonstrated patent by arteriogram before the animals were killed. The mean intimal area of the saphenous vein grafts was increased when compared with that of the nongrafted saphenous veins (2.83 mm(2) vs 0.09 mm(2), P <.0008). Adenoviral-treated saphenous vein grafts demonstrated positive transgene expression either by X-gal staining (beta-galactosidase) or Northern analysis (beta-adrenergic receptor kinase carboxyl terminus).


CONCLUSIONS
This study characterizes a clinically relevant canine model of aortocoronary saphenous vein graft intimal hyperplasia. In addition, it demonstrates that adenoviral vectors can be delivered ex vivo to the saphenous vein graft vessel wall at subphysiologic distension pressures. This model may be used in future studies to manipulate molecular targets critical in aortocoronary saphenous vein graft intimal hyperplasia.
Petrofski
Jason A
JA
Department of Surgery, Duke University Medical Center, Durham, NC 27703, USA.
Hata
Jonathan A
JA
Gehrig
Thomas R
TR
Hanish
Steven I
SI
Williams
Matthew L
ML
Thompson
Richard B
RB
Parsa
Cyrus J
CJ
Koch
Walter J
WJ
Milano
Carmelo A
CA
D000818:Animals; D001027:Aortography; D001707:Biopsy, Needle; D001026:Coronary Artery Bypass / Q000379:methods*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006083:Graft Occlusion, Vascular / Q000000981:diagnostic imaging / Q000517:prevention & control*; D006965:Hyperplasia / Q000000981:diagnostic imaging / Q000517:prevention & control; D007150:Immunohistochemistry; D008297:Male; D011336:Probability; D018570:Risk Assessment; D012501:Saphenous Vein / Q000473:pathology / Q000637:transplantation*; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D017539:Tunica Intima / Q000473:pathology*; D014654:Vascular Patency / Q000502:physiology