Sustained retention of tetradecylthioacetic acid after local delivery reduces angioplasty-induced coronary stenosis in the minipig.
OBJECTIVE
The sulfur containing tetradecylthioacetic acid (TTA) has a profound effect on lipid metabolism and may also exert antioxidant and anti-inflammatory actions and thereby counteract coronary stenosis after angioplasty balloon injury. This study examined the possible modulatory effects of TTA, delivered locally, on coronary stenosis in minipigs and the underlying mechanisms of action.


METHODS
Coronary balloon angioplasty injury using an oversized balloon was performed to 40 coronary arteries (20 minipigs, Sus Scrofa, Gammelsroed) followed by delivery of placebo or TTA via a local drug delivery balloon catheter. TTA was radiolabelled in four pigs. Quantitative coronary angiography and intracoronary ultrasound (ICUS) were performed before and after injury, and after 4 weeks of follow-up. The arteries were examined with histomorphometry. The antioxidant and anti-inflammatory effects of TTA were examined on LDL oxidation and stimulated release of interleukin (IL)-2 and IL-10 in human peripheral blood mononuclear cells (PBMC), respectively.


RESULTS
Radioactive TTA was present in the coronary wall after 4 weeks. Angiographic minimal luminal diameter (mean+/-S.E.M.) in the placebo and TTA group was 1.3+/-0.1 vs. 2.2+/-0.2 mm (P<0.01) at follow-up, stenosis rate was 55 and 20% (P<0.01). Remodeling was -0.56+/-0.12 in the TTA group and -1.28+/-0.09 in the placebo group (P<0.01). TTA significantly prolonged the lag time of LDL oxidation. In phytohemagglutinin stimulated PBMC, TTA significantly decreased IL-2 levels and increased IL-10 levels suggesting a marked anti-inflammatory net effect.


CONCLUSIONS
Local delivery of TTA reduces coronary artery stenosis after PTCA as assessed by both angiographic, histomorphometric and ICUS examinations by influencing vessel remodeling rather than intimal hyperplasia. The underlying mechanism(s) seem to involve antioxidant and anti-inflammatory effects of this fatty acid analogue.
Pettersen
R J
RJ
Department of Heart Disease, Haukeland University Hospital, N-5021, Bergen, Norway. rpet@haukland.no
Muna
Z A
ZA
Kuiper
K K
KK
Svendsen
E
E
Müller
F
F
Aukrust
P
P
Berge
R K
RK
Nordrehaug
J E
JE
D000287:Administration, Topical; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003300:Copper; D017023:Coronary Angiography; D023921:Coronary Stenosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000293:injuries* / Q000378:metabolism; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D010084:Oxidation-Reduction; D013440:Sulfides / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D013556:Swine, Miniature; D018084:Ultrasonography, Interventional
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D007376:Interleukin-2; D008077:Lipoproteins, LDL; D013440:Sulfides; D016753:Interleukin-10; D003300:Copper; C062078:1-(carboxymethylthio)tetradecane