New efficient catheter-based system for myocardial gene delivery.
BACKGROUND
Manipulating gene expression in the failing heart has therapeutic promise, but until now efficient and homogeneous cardiac gene delivery has required an open-chest approach. This study examines the hypothesis that vector delivery promoted by echo contrast microbubbles will be maximized by injection of the vectors into the aortic root with brief balloon occlusion above the sinuses, while at the same time prolonging diastole and vasodilating with acetylcholine (ACh) to maximize coronary exposure.


RESULTS
After incubation with albumin-coated perfluorocarbon microbubbles, an adenovirus encoding a reporter gene was infused into the aortic root of rats. To maximize delivery, the aortic root was transiently occluded with a balloon catheter during a brief ACh-induced asystole. Ultrasound was used to image the delivery and disrupt the microbubbles. Aortic occlusion with concomitant ACh increased myocardial gene expression for virus + microbubbles by >2.5-fold, from 925+/-165 to 2358+/-376 relative units (RU; P<0.01). This delivery system also produced substantial expression with vector alone (1473+/-549 RU). All uptakes were significant compared with 433+/-332 RU without virus.


CONCLUSIONS
An adenoviral delivery system combining echo contrast with a catheter-based technique to maximize coronary perfusion increases gene delivery compared with echo contrast alone. This novel method permits efficient percutaneous gene delivery in closed-chest animals.
D000109:Acetylcholine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006328:Cardiac Catheterization / Q000379:methods*; D002339:Carotid Arteries / Q000502:physiology; D002404:Catheterization; D004337:Drug Carriers; D017548:Echocardiography, Transesophageal; D005466:Fluorocarbons; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006321:Heart / Q000187:drug effects*; D007269:Injections, Intra-Arterial; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D009928:Organ Specificity; D051381:Rats; D011917:Rats, Inbred Lew; D012850:Sinus of Valsalva / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D004337:Drug Carriers; D005466:Fluorocarbons; D014665:Vasodilator Agents; D001616:beta-Galactosidase; D000109:Acetylcholine