Figure 2. (a) Adenoviral transfection of luciferase reportergene DNA revealed a modest effect after antegrade infusion into the region of interest (LAD-perfused area), even though the venous outflow was blocked by a balloon in the anterior interventricular vein). (b) Retroinfusion itself, however, increased reportergene expression in the corresponding area significantly (modified from Boekstegers et al., Gene Therapy 2000). (c) In comparison to the percutaneous intramyocardial delivery (PIMD) using a needle catheter, or surgical intramyocardial delivery (SIMD) after lateral thoracotomy, percutaneous retrograde delivery of adenoviral galactosidase revealed a more homogenous and in part more efficient transfection mode of the viral contact time - as shown by intramyocardial injections and local gene delivery into the wall of coronary arteries - substantially increased transfection and gene expression [35-37].

In order to solve this limitation of intraarterial gene delivery, percutaneous transluminal retrograde gene delivery (PTRGD) through the coronary veins was applied in preclinical studies by several groups recently. The efficacy and selectivity of percutaneous retrograde transluminal gene delivery (PTRGD) using continuous pressure-regulated retroinfusion was first studied in pigs [17]. In order to optimize percutaneous transluminal adenoviral gene delivery, antegrade intracoronary and retrograde coronary venous delivery were compared (Figure 2), revealing a clearcut increase in efficacy even though antegrade delivery was combined with retrograde outflow blockade. Notably, blocking the antegrade inflow during retroifn-suion, reporter gene expression was distributed more homogeneously throughout the myocardium [17]. Moreover, selective targeting of the adenoviral vectors to the retroinfused myocardial region was revealed, since reporter gene activity in the non-targeted CX-region stayed at background levels.

Although intramyocardial injection has been considered to be the preferred delivery strategy by many investigators [38-41], a more homogenous but equally efficient delivery might be the prerequisite to substantially influence regional myocardial blood supply or function by angiogenic or arteriogenic substrates. Until recently, however, a direct comparison of gene delivery by selective pressure-regulated retroinfusion to intramyocardial injection techniques has not been performed [42]. Surprisingly, overall gene expression in the targeted LAD region after adenoviral gene transfer was even more pronounced after selective retroin-fusion than after intramyocardial injection [4]. As expected, selective retroinfusion led to a more homogeneous transmural gene transfer if compared to either surgical or percutaneous intramyocardial injection in the same model (Figure 2c).

In summary, adenoviral mediated reporter gene transfer was substantially increased by selective pressure-regulated retroinfusion through the coronary veins as compared to antegrade delivery into the coronary artery. This observation was consistent in either ischemic or nonischemic myocardium. Selective retroinfusion compared also favorably to either surgical or percutaneous intramyocardial injection techniques.

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