Paradoxical effects of aurintricarboxylic acid and RG-13577: acute thrombosis and in-stent stenosis in a passive-coated stent.
OBJECTIVE
To investigate if a platelet inhibitor (aurintricarboxylic acid [ATA]) and a heparin-mimicking antagonist (RG-13577) of basic fibroblast growth factor 2 (bFGF2) could be combined as a stable compound and attached to conventional bare metal stents to hinder thrombus formation and inflammatory reactions of stenting.


METHODS
Fifteen domestic pigs were stented with RG-13577/ATA-coated (n=6), ATA-coated (n=12), and bare metal stents (n=12) in the left anterior descending (LAD) and left circumflex (LCX) coronary arteries. All surviving pigs were evaluated with contrast angiography and intravascular ultrasonography (IVUS) after 4 weeks. Histological analysis of the stented arteries was performed after hematoxylin-eosin staining. Tissue factor (TF) staining and scanning electron microscopy (SEM) were performed in animals with acute stent thrombosis.


RESULTS
Five of the 6 animals receiving an RG-13577/ATA-coated stent experienced acute stent thrombosis, while no adverse events occurred in the animals of the other 2 groups. Follow-up angiography did not show significant in-stent stenosis in either bare or ATA-coated stents. However, histomorphometry revealed larger neointimal area (3.54+/-0.69 mm2 versus 1.82+/-0.27 mm2, p<0.05) and outward plaque area (1.56+/-0.34 mm2 versus 0.61+/-0.12 mm2, p<0.05) in ATA-coated stents. Three-dimensional IVUS analysis showed analogous results, with significantly larger neointimal volume and outward plaque volume in ATA-coated stents. There was a slight increase in TF staining around the stent struts, while SEM showed increased platelet adhesion and activity in RG-13577/ATA-coated stents versus the ATA-coated and bare metal stents.


CONCLUSIONS
RG-13577/ATA-coated stents lead to acute stent thrombosis. The ATA coating alone did not lead to acute events, but resulted in higher neointimal hyperplasia and expansive remodeling. These results underline the importance of preclinical studies before using new coated stents in human arteries.
Strehblow
Christoph
C
Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Austria, and Departmetn of Cardiology, Karolinska University Hospital at Huddinge, Stockholm, Sweden. Christoph.Strehblow@wienkav.at
Sperker
Wolfgang
W
Hevesi
Akos
A
Garamvölgyi
Rita
R
Petrasi
Zsolt
Z
Shirazi
Maryam
M
Sylvén
Christer
C
Weiss
Thomas
T
Lotan
Chaim
C
Pugatsch
Thea
T
Ben-Sasson
Shmuel A
SA
Orlowski
Michael
M
Glogar
Dietmar
D
Gyöngyösi
Mariann
M
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000517:prevention & control; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D006965:Hyperplasia; D008855:Microscopy, Electron, Scanning; D010642:Phenoxyacetates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D011108:Polymers / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D015607:Stents / Q000009:adverse effects; D013552:Swine; D013927:Thrombosis / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D017211:Treatment Failure; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D004338:Drug Combinations; D010642:Phenoxyacetates; D010975:Platelet Aggregation Inhibitors; D011108:Polymers; D016222:Fibroblast Growth Factor 2; C090697:2-(4-hydroxyphenoxy)acetic acid-formaldehyde polymer; D001312:Aurintricarboxylic Acid