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.

Tetradecylthioacetic acid reduces stenosis development after balloon angioplasty injury of rabbit iliac arteries.

BACKGROUND: tetradecylthioacetic acid (TTA) is a synthetic long-chain fatty acid analogue that inhibits the oxidative modification of low-density lipoprotein particles in vitro. We examined the influence of TTA on the arterial wall response after balloon angioplasty injury in a rabbit iliac model. METHODS AND RESULTS: 14 rabbits were randomized to receiving either TTA fatty acids 800 mg daily perorally (weight 3.6+/-0.1 kg) or to normal diet (weight 3.5+/-0.5 kg, P=NS). Angioplasty was performed via right carotidotomy on both iliac arteries using an oversized balloon catheter, the TTA group being pretreated for 3 weeks. After angioplasty, the lumen diameter was 2.37+/-0.18 versus 2.36+/-0.13 mm for the TTA and control groups, respectively (P=NS). At 10 weeks follow-up angiography, minimal luminal diameter was 1.64+/-0.27 versus 1.13+/-0.52 mm for the TTA and control groups respectively (P<0.05). Histomorphometry did not show significant differences in intimal hyperplasia between the two groups (maximal intimal thickness 0.22+/-0.04 versus 0.19+/-0.10 mm, P=NS and intimal area 0.32+/-0.12 versus 0.36+/-0.23 mm(2), P=NS for the TTA and the control groups, respectively). In the heart, the sum of the n-3 fatty acids was 8.9+/-2.7 in the TTA group versus 4.3+/-0.2 mol% in the control group (P<0.05). The anti-inflammatory fatty acid index, calculated as (22:5 n-3+22:6 n-3+20:3 n-6)/20:4 n-6, was 0.76+/-0.10 vs. 0.25+/-0.03 for the TTA and control groups, respectively (P<0.05). In vitro TTA (100 microM) reduced the proliferation of human smooth muscle cell by more than 50%. CONCLUSION: treatment with TTA is associated with positive arterial remodeling after angioplasty injury. The significance of the in vitro inhibition of human smooth muscle cell proliferation needs to be further elucidated.

Long-term retention of a novel antioxidant sulphur-substituted fatty acid analogue after local delivery in porcine coronary arteries.

OBJECTIVE: Antioxidants have been suggested to reduce restenosis after balloon angioplasty. A novel sulphur-containing fatty acid, tetradecylthioacetic acid (TTA), with antioxidant properties, is efficiently incorporated into cellular phospholipids. We have determined the uptake and retention of TTA after local coronary artery delivery in 20 pigs. DESIGN: Radiolabelled TTA was delivered to 40 main coronary arteries via a multiporous coronary angioplasty balloon catheter inflated before, after, or without overstretch vessel injury. The animals were killed at intervals of up to 6 weeks post-procedure. The radioactivity of the tissue sections was determined as nmol TTA/g tissue. RESULTS: Concentrations of TTA in the coronary arteries were 1.84 +/- 0.45 nmol/g up to 24 h, 1.50 +/- 0.96 nmol/g at 2 weeks, 0.22 +/- 0.11 nmol/g at 4 weeks and a trace was present at 6 weeks (p-value for trend <0.01). The arterial wall uptake at the delivery site was higher than distal to delivery (1.84 +/- 0.37 vs 0.55 +/- 0.13 nmol/g, p = 0.006) and perivascular fat (p < 0.01) but not higher than in the myocardium. Infusion before, after or without vessel injury was not important for tissue concentration. CONCLUSIONS: After local coronary artery delivery, the antioxidant TTA is taken up by the arterial wall in which it is retained for at least 4 weeks.

Early mobilization after protamine reversal of heparin following implantation of phosphorylcholine-coated stents in totally occluded coronary arteries.

Immediate removal of the femoral artery sheath after coronary angioplasty may allow rapid mobilization and reduces the number of in-hospital days. We studied the early and 1-month clinical and angiographic follow-up of patients having heparin reversed with protamine after implantation of phosphorylcholine-coated metal (Divysio) stents, followed by removal of the femoral artery sheath. Fifty patients (37 men, mean age 59 +/- 10 years) with stable angina pectoris and a single totally occluded artery (1 unprotected left main stem, 15 left anterior descending, 11 left circumflex, 23 right) underwent coronary angioplasty. Antithrombotic medication was salicylic acid 75 to 160 mg before, heparin bolus 7,500 IU during, and protamine sulfate 25 mg and oral ticlopidine 250 mg after the procedure. Angiography was performed after 30 minutes and at 1 month. The mean number of stents was 1.4 +/- 0.6/lesion, with a mean final diameter of 2.69 +/- 0.40 mm. One stent thrombus was detected after 30 minutes and was treated with balloon dilatation. One patient underwent emergency bypass surgery for non-stent-related problems. Forty-six patients were mobile after 5 hours, and 2 after >5 hours. At 1 month there had been no major coronary end points, rehospitalizations, groin bleeding, or more thrombi. One episode of transient pulmonary edema occurred after protamine injection. Thirty-eight patients (79%) had no angina at 1 month, maximal bicycle exercise capacity increased from 128 +/- 42 to 160 +/- 45 W (p <0.05), and left ventricular ejection fraction increased from 63% to 68% (p <0.05). Thus, reversal of heparin with protamine sulfate after implantation of a phosphorylcholine-coated stent enables early mobilization. This approach seems safe in patients with 1 -vessel total occlusions and angioplasty could be performed as an outpatient procedure.

Phosphorylcholine-coated metallic stents in rabbit iliac and porcine coronary arteries.

The arterial wall reaction to phosphorylcholine-coated metal stents was examined in rabbits and pigs. Compared to non-coated stents, no significant difference was found by angiography and histology. We conclude that although phosphorylcholine-coating does not provoke arterial neointima formation or decrease luminal diameter compared to stainless steel stents, the coating does not seem to reduce restenosis.

Ketorolac (Toradol) as an analgesic in swine following transluminal coronary angioplasty.

Post-procedure pain is a common complication in swine following survival angioplastic procedures. Ketorolac and buprenorphine have been used to control pain in these animals. Time from completion of procedure-extubation to onset of feeding was used as an indicator for analgesic effect. The onset of feeding following extubation occurs within 6 to 20 h in animals given ketorolac compared to 30 plus hours in animals given buprenorphine.