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Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins

Comparison with surgical and percutaneous intramyocardial gene delivery

Philip Raake, MD^*, Georges von Degenfeld, MD^*, Rabea Hinkel, DVM^*, Robert Vachenauer^*, Torleif Sandner^*, Sabrina Beller^*, Martin Andrees^*, Christian Kupatt, MD, PhD^*, Gerhard Schuler, PhD and Peter Boekstegers, PhD^*,*

^* Internal Medicine I, Grosshadern University Hospital, Munich, Germany
Department of Cardiology, Heart Center, University of Leipzig, Leipzig, Germany

Manuscript received January 15, 2004; revised manuscript received April 28, 2004, accepted May 3, 2004.

^* Reprint requests and correspondence: Dr. Peter Boekstegers, Medizinische Klinik I, Klinikum Grosshadern, Marchioninistr. 15, D-81377 München, Germany (Email: boekstegers{at}med1.med.uni-muenchen.de).

OBJECTIVES: We sought to study adenoviral gene delivery using percutaneous selective pressure-regulated retroinfusion and to compare it directly with surgical and percutaneous intramyocardial delivery (PIMD) for the first time.

BACKGROUND: Intramyocardial delivery (IMD) has been recommended to be the preferred gene delivery strategy so far. However, surgical and percutaneous intramyocardial injection lead to incomplete retention of the injected viral vectors and to limited spatial myocardial distribution. Percutaneous selective pressure-regulated retroinfusion of the coronary veins was developed recently to provide an effective and more homogenous regional myocardial gene transfer.

METHODS: In 15 pigs, adenoviral vectors (Ad2-CMV beta-galactosidase [ß-gal] 5 x 10⁹ pfu) were applied via surgical IMD (n = 5), PIMD (n = 5), and selective pressure-regulated retroinfusion (n = 5). Seven days after gene transfer, myocardial ß-gal expression was measured by ELISA.

RESULTS: Selective retroinfusion into the anterior cardiac vein substantially increased reporter gene expression (1,039 ± 79 pg ß-gal/mg protein) in the targeted left anterior descending coronary artery territory when compared with surgical (448 ± 127, p < 0.05) and PIMD (842 ± 145, p < 0.05). Both IMD approaches showed an inhomogenous ß-gal expression, particularly along the injection sites, while retroinfusion resulted in a more homogenous transmural gene expression.

CONCLUSIONS: Percutaneous selective pressure-regulated retroinfusion compares favorably with surgical and percutaneous intramyocardial injection techniques by providing a more homogenous and even more efficient adenoviral gene delivery.

Abbreviations and Acronyms   ENDO = endomyocardial (probe or layer)   EPI = epicardial (probe or layer)   IMD = intramyocardial delivery   LAD = left anterior descending (coronary artery)   LV = left ventricle/ventricular   MID = midmyocardial (probe or layer)   PIMD = percutaneous intramyocardial delivery   ß-gal = beta-galactosidase

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