© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium
aDivision of Cardiovascular and Thoracic Surgery, Box 3857, Duke University Medical Center, Durham, NC 27710, USA
bDivision of Cardiology, Box 3857, Duke University Medical Center, Durham, NC 27710, USA
* Corresponding author. Tel.: +1-919-684-5059; fax: +1-919-681-7054 chadh{at}acpub.duke.edu
Objective: Transmyocardial laser revascularization (TMR) is emerging as a potential treatment option for patients with end-stage CAD, and adjuvant gene therapy may be helpful in further improving the results of the procedure. However, the effects of TMR on gene transfer are unknown. Methods: Swine underwent left thoracotomy. TMR was performed to create five channels at 2-cm intervals in the anterolateral free wall of the left ventricle (LV) followed by injection of 1x109 plaque-forming units (pfu) of a replication-deficient adenovirus vector carrying the reporter gene β-galactosidase (Ad.Pac β-gal). An additional five direct injections of 1x109 pfu Ad.Pac β-gal were made at 2-cm intervals in the posterolateral LV of each heart. Control animals underwent TMR alone/vehicle alone (n=3) or empty virus alone/no treatment (n=3) of the anterolateral/posterolateral LV, respectively. Results: ELISA revealed significantly greater transgene expression in the direct Ad.Pac β-gal injection versus TMR plus Ad.Pac β-gal inject regions at both 3 (n=6) (273.0±58.5 vs. 133.4+28.1 pg β-gal/g protein, P=0.02) and 7 days (n=6) (180.0+59.9 vs. 56.7+18.1 pg β-gal/g protein, P=0.02) postoperatively. At 14 days postoperatively (n=2), no transgene expression was detected in either region. No transgene expression was detected in any of the control regions at 3 days postoperatively. CD-18 staining revealed significantly greater inflammation in the TMR plus Ad.Pac β-gal and TMR alone regions as compared to Ad.Pac β-gal or vehicle (P<0.001). Conclusions: Adenoviral-mediated gene transfer in conjunction with TMR is possible, although TMR appears to limit the degree of transgene expression attained as compared to direct intramyocardial injection alone, likely due to the greater immune response observed with the former. These findings may have important implications for therapeutic strategies aimed at combining TMR with gene therapy for CAD.
KEYWORDS Cardiovascular surgery; Coronary disease; Gene therapy; Gene expression; Inflammation; Swine
Presented in part at the American College of Cardiology 48th Annual Scientific Session, March 7–10, 1999, New Orleans, Louisiana, USA.
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