Abstract
Strictly intravascular approaches for the treatment of postangioplasty restenosis are effective in the intima and the inner parts of the media but may be insufficient to control redundant pathways in the more outer parts of the media and the adventitia. An inverse situation may occur subsequently to a strictly extravascular approach, like the recently suggested pericardial approach in pigs. We hypothesized that simultaneous intra/extravascular administration of anti-restenotic agents inhibits restenosis by blocking all stimulatory pathways in the entire arterial wall. Fresh hearts of 25 domestic pigs were obtained from a local slaughterhouse. Left anterior descending coronary arteries (LAD) were harvested, cut into cylindric 5 mm segments, and cultured as ex vivo porcine organ cultures (POCs). After 9 bar ballooning simultaneous intra/extravascular administration of high dose diltiazem (50 microg/mL) was carried out for a period of 1, 2, 3, 4, 5, 6, and 7 days. At day 7 and 28 proliferative activity (BrdU), neointimal thickening, and staining against smooth muscle alpha-actin and vWF was analysed. 7 days after ballooning administration of diltiazem for 4, 5, 6, and 7 days inhibited reactive cell proliferation by more than 50% (n.s.) as compared to control, 28 days after ballooning administration for 6 and 7 days inhibited neointimal thickening by more than 75% (p < 0.05). Simultaneous intra/extravascular administration of high dose diltiazem did not affect the expression of vWF in endothelial cells or smooth muscle alpha-actin in smooth muscle cells. Simultaneous intra/extravascular administration of high dose diltiazem (50 microg/mL) has to be maintained for at least 6 days to achieve a significant inhibition of neointimal thickening. The data demonstrate the importance of the maximal reactive cell proliferation (= day 7 in the POC-model) for the calculation of the duration of the treatment period.
Highlights
Despite the outstanding success of coronary angioplasty and related techniques the problem of restenosis [1] has not yet been overcome
After simultaneous intra/extravascular administration of diltiazem for 1 and 2 days the number of BrdUpositive cells was 2.8 ± 6.1% and 1.1 ± 1.8% corresponding to an inhibition by 36 respectively 75%
After incubation of porcine organ cultures (POCs)-segments with diltiazem for 4, 5, 6, and 7 days the percentage of BrdU-positive cells was 0.8 ± 1.1%, 1.9 ± 3.6%, 0.3 ± 0.7%, and 1.2 ± 1.8% corresponding to an inhibition by 81%, 57%, 93%, and 72%. 28 days after ballooning the number BrdU-positive cells was very small, 0.0 ± 0.0% of BrdU-positive cells were detected in untreated controls and in the POC balloon-group
Summary
Despite the outstanding success of coronary angioplasty and related techniques the problem of restenosis [1] has not yet been overcome. In a very schematic way the main events after coronary artery ballooning are dissection, elastic recoil, thrombosis, leukocyte attack, reactive cell proliferation, and arterial remodeling [2] Among these reactive cell proliferation remains extremely difficult to control, many therapeutical agents have a strong antiproliferative effect [3]. Intravascular anti-restenotic drug regimens are predominantly effective in the inner layers of the artery wall, upregulation of redundant pathways in the outer parts of the media and the adventia are not or not entirely inhibited. We hypothesized that simultaneous intra/extravascular administration of antiproliferative agents inhibits restenosis by blocking all redundant pathways [4]. We hypothesized that simultaneous intra/extravascular administration of anti-restenotic agents inhibits restenosis by blocking all stimulatory pathways in the entire arterial wall
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