Catheter-based intracoronary myocardial adenoviral gene delivery: importance of intraluminal seal and infusion flow rate.
Although percutaneous, adenoviral-mediated intracoronary gene delivery to the heart has been demonstrated in some species, consistent and safe methodology is needed before clinical applicability is possible. In this study, we examine the effects of altering intracoronary flow rate and obtaining an adequate seal between the catheter and the coronary lumen on successful cardiac gene delivery and myocardial injury in both piglets and adult rabbits. To study the efficacy of in vivo myocardial gene transfer, we utilized adenoviral vectors containing either the beta(2)-adrenergic receptor or beta-galactosidase. The left circumflex coronary artery of piglets and the right coronary artery of rabbits were catheterized under fluoroscopic guidance and adenovirus solutions were injected using varying flow rates with or without balloon inflation. Successful transgene delivery to the heart was determined approximately 1 week after coronary infusions. Histologic analysis was also performed in all animals to determine the extent of myocardial injury. Our results indicate that efficient and reproducible cardiac transgene expression utilizing intracoronary delivery is dependent upon the infusion flow rate and, in larger animals, requires an intraluminal seal. Excessive flow rate is associated with greater myocardial injury. Thus, conditions can be established and controlled to improve future investigational and clinical application of catheter-based intracoronary myocardial gene therapy.
Emani
Sitaram M
SM
Department of Surgery, Durham, North Carolina 27710, USA.
Shah
Ashish S
AS
Bowman
Michael K
MK
Emani
Sitaramesh
S
Wilson
Katrina
K
Glower
Donald D
DD
Koch
Walter J
WJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002404:Catheterization / Q000009:adverse effects / Q000295:instrumentation* / Q000379:methods*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D011312:Pressure; D011817:Rabbits; D012212:Rheology; D013552:Swine; D019076:Transgenes / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
D001616:beta-Galactosidase