Paclitaxel-induced arterial wall toxicity and inflammation: part 2--long-term tissue response in a minipig model.
OBJECTIVE
In part 1 of the present study, the authors demonstrated that coronary paclitaxel uptake from drug eluting stents (DESs) was not dependent on exposure time and dose. In this second part, the effect of the different paclitaxel dose densities on long-term biologic behavior was evaluated.


METHODS
In 40 minipigs, (with 4- and 12-week follow-up), identical stents with the same three paclitaxel dose densities as in part 1 were implanted in the right coronary artery. Minipigs implanted with Polyzene-F nanocoated stents served as the control group. Quantitative angiography measuring average luminal diameter (from three in-stent reference points), minimal luminal diameter (from the point of maximum in-stent stenosis), average late loss, maximum late loss, and binary stenosis rate was performed, as was microscopy to determine neointimal thickening, injury score, and inflammation.


RESULTS
All three DESs were associated with a high average late loss, binary stenosis rate, and neointimal thickening, without significant differences. Drug-free stents had significantly less late in-stent stenosis: there was an average late loss of 0.3 mm +/- 0.3 in drug-free stents versus 0.8 mm +/- 0.2 in intermediate-dose stents and 1.5 mm +/- 0.6 in high-dose stents (P = .04). DES-associated inflammation was high in all DESs and six times higher as in the drug-free stents (Kornowski scores of 0.2 +/- 0.1 in drug-free stents, 1.3 +/- 0.9 in low-dose stents, 1.7 +/- 0.8 in intermediate-dose stents, and 1.3 +/- 1.0 in high-dose stents; P = .04). It worsened with time in all DESs, as did late in-stent stenosis.


CONCLUSIONS
The extensive and long-term retention of paclitaxel even in a low-dose formulation, at least according to the present labeling of DESs, might be associated with negative long-term results with regard to inflammation and late in-stent stenosis.
Stampfl
Ulrike
U
Department of Radiology, University of Heidelberg Medical Center, INF 110, 69120 Heidelberg, Germany.
Radeleff
Boris
B
Sommer
Christof
C
Stampfl
Sibylle
S
Lopez-Benitez
Ruben
R
Thierjung
Heidi
H
Kurz
Patrick
P
Berger
Irina
I
Richter
Goetz M
GM
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000295:instrumentation*; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000633:toxicity*; D020099:Coated Materials, Biocompatible; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D005260:Female; D007249:Inflammation / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D023421:Models, Animal; D017239:Paclitaxel / Q000008:administration & dosage / Q000633:toxicity*; D011474:Prosthesis Design; D011475:Prosthesis Failure; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
D002317:Cardiovascular Agents; D020099:Coated Materials, Biocompatible; D017239:Paclitaxel