Dose-dependent coronary artery intimal thickening after local delivery of the anti-oxidant tetradecylthioacetic acid from stents.

OBJECTIVE: To examine the in vitro uptake and elution of the anti-oxidant tetradecylthioacetic acid (TTA) from phosphorylcholine (PC)-coated stents, and the in vivo uptake, retention, inflammatory response and histomorphometric changes after overstretch injury of the porcine coronary artery. METHODS: PC-coated stents were loaded in one of three different concentrations of TTA (87, 174 and 347 mmol/L, i.e. 25, 50 and 100 mg/mL) and randomized versus PC-coated stents to the right coronary or left circumflex artery (18 pigs). Uptake of TTA into the coronary wall from the 347 mmol/L concentration was measured after 3 h and 24 h, 7 days, 14 days and 28 days (two pigs at each time point). RESULTS: In vitro, TTA was successfully loaded onto the stents and elution was nearly complete after 48 h. In vivo, TTA could be demonstrated in the vessel wall for up to 4 weeks. Percent area stenosis was significantly higher in the TTA group, 35.2+/-20.9% versus 27.5+/-17.0% (p=0.03). Dose-related comparison showed increased intimal thickness, 0.66+/-0.53 mm versus 0.29+/-0.26 mm (p=0.008) and intimal area, 2.83+/-1.61 mm2 versus 1.58+/-0.91 mm2 (p=0.004) for the 347 mmol/L TTA versus controls. There was a significantly positive relationship between the TTA-loading dose and both intimal area (B=0.69, p=0.01) and maximal intimal thickness (B=0.17, p=0.02). The pro-inflammatory precursor arachidonic acid increased four-fold in the arterial wall of the TTA group, while the anti-inflammatory fatty acid index, calculated as (docosapentaenoic acid+docosahexaenoic acid+dihomo-linolenic acid)/arachidonic acid, was suppressed to 0.65+/-0.27 compared to 1.13+/-0.23 in control vessels (p<0.001). CONCLUSION: TTA caused a dose-dependent intimal thickening and reduced anti-inflammatory fatty acid index. Contrary to expectations, TTA seems unsuitable as stent coating.

Inhibition of rat lipoprotein oxidation after tetradecylthioacetic acid feeding.

We have previously shown that tetradecylthioacetic acid (TTA), a sulfur containing saturated fatty acid analogue, inhibits the oxidative modification of human low-density lipoprotein (LDL) in vitro. The oxidative modification of LDL is believed to be a crucial step in the progression of atherosclerosis. In the present study, we investigated the effect of TTA oral administration on the susceptibility of rat lipoprotein to undergo oxidative modification ex vivo. Lipoprotein resistance to copper-induced oxidation was highly improved after TTA administration to rats. Conjugated dienes produced after 150 min of lipoprotein oxidation were dramatically lowered in the TTA treated rats compared to controls. Malondialdehyde and lipid peroxides production by oxidation was highly limited. These effects were independent of any Vitamin E effects. More than 50% relative reduction in polyunsaturated fatty acids of the n-3 family, and more than 30% relative increase in 18:1n-9 fatty acid in the triacylglycerol (TAG)-rich lipoprotein were observed. TAG-rich lipoprotein lipids of TTA fed rats were decreased with more than 50% reduction in TAG. The data reported in this paper indicate a potent in vivo antioxidant capability of TTA that beside its hypolipidemic effect might be of importance in relation to the development of atherosclerosis.