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Cardiovascular Research 2001 52(2):306-313; doi:10.1016/S0008-6363(01)00404-7
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Copyright © 2001, European Society of Cardiology

Sustained retention of tetradecylthioacetic acid after local delivery reduces angioplasty-induced coronary stenosis in the minipig

Reidar J. Pettersena,*, Ziad A. Munab, Karel K.J. Kuipera, Einar Svendsenc, Fredrik Müllerd, Pål Aukruste, Rolf K. Bergeb and Jan Erik Nordrehauga

aDepartment of Heart Disease, Haukeland University Hospital, N-5021 Bergen, Norway
bDepartment of Clinical Biochemistry, Haukeland University Hospital, N-5021 Bergen, Norway
cDepartment of Pathology, Haukeland University Hospital, N-5021 Bergen, Norway
dResearch Institute for Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway
eSection of Clinical Immunology and Infectious Disease, Rikshospitalet, N-0027 Oslo, Norway

* Corresponding author. Tel.: +47-55-972-220; fax: +47-55-975-150 rpet{at}haukland.no

Received 7 March 2001; accepted 28 June 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
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.

KEYWORDS Angioplasty; Arteries; Coronary disease; Infection/inflammation


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
Formation of atherosclerotic lesions is a multicellular process in which lipids and extracellular matrix accumulate on the intima of arteries, and a local inflammatory response is elicited due to the activation of macrophages, T-lymphocytes, smooth muscle and endothelial cells [1,2]. Restenosis, after percutaneous transluminal coronary angioplasty (PTCA) or other interventional therapy, has been considered an accelerated version of this process induced by arterial-wall injury and a wound–healing response to severe intimal and medial damage [3,4]. The mechanisms leading to restenosis have not been fully clarified, but may involve enhanced oxidative stress [5] and increased release of pro-inflammatory cytokines [6]. Indeed, antioxidant therapy inhibited the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits [7,8], and some reports suggest beneficial effects of antioxidants conferring reduction of restenosis in humans [9,10].

Tetradecylthioacetic acid (TTA), which has profound effect on lipid metabolism when administered orally to rats [11], activates both peroxisome proliferator-activated receptors (PPAR) {alpha} and {gamma} [12], and may also have antioxidant properties as it contains a sulfur atom. In addition, considering the role of PPARs in both lipid metabolism and inflammatory responses [13], we hypothesized a function for TTA at the level of the vascular wall, which independent of its role in lipid metabolism [11], could modulate the pathogenesis of restenosis. In the present study, we examined the possible modulatory effects of TTA on restenosis by different experimental approaches. Firstly, we studied the temporal retention of TTA after local drug delivery. Secondly, we studied the effect of TTA on the development of stenosis after balloon angioplasty injury of normal porcine coronary arteries by introducing TTA locally using a transport multiporous angioplasty balloon catheter. Thirdly, we studied the antioxidant properties of TTA by examining the ability of this fatty acid to impair copper induced LDL oxidation. We also studied the possible anti-inflammatory effects of TTA by examining its ability to modulate cytokine production in peripheral blood mononuclear cells.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 Acknowledgments
 References
 
2.1 Animals
Minipigs (Sus Scrofa, Gammelsroed) of either sex, weight 33–40 kg, were fed twice daily on a Standard pig feed®, without cholesterol supplementation, 7–10 days before the procedure. The experimental work was performed in the animal laboratory of the Haukeland University Hospital. The animals were kept under controlled environmental conditions and sacrificed 4 weeks post-procedure. The local ethics for animal-care and use approved the study-protocol. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.2 Procedure
Twenty minipigs were randomized to placebo or active treatment in 40 coronary arteries. An 8F multipurpose hockey stick coronary guiding catheter was advanced via the right femoral artery. Coronary artery injury was performed to the left anterior descending artery or to the left circumflex artery according to randomization using an oversized semicompliant 20 mm long angioplasty balloon catheter. The balloon was expanded to 12 atmospheres for 30 s with balloon/vessel ratio 1.2:1.3. The balloon was placed in relation to an easily recognizable anatomical structure, i.e. the large side branch.

Aspirin 300 mg was given by mouth to each animal (approximately 8 mg/kg body weight) in the evening before and in the morning of the procedure day. Sedation was induced by a mixture of Ketamine (10 mg/kg), Methomedine (0.1 mg/kg) and 1 mg atropine. General anesthesia was achieved by a gas stream of 5% Isoflurane® (Forene, Abbot) in 40% oxygen and 60% Nitrous Oxide. The depth of anesthesia was evaluated in each animal. Electrodes were placed on the chest for continuous electrocardiographic monitoring. The anesthesia was supplemented by Ketamine® and Diazepam® intravenously. A bolus of 100 IU/kg heparin was administered intra-arterially before angioplasty.

2.3 TTA preparation
TTA and radiolabelled TTA were synthesized as described earlier [14,15]. TTA solution was prepared as follows: TTA was dissolved in 0.9% saline and heated to approximately 75°C to achieve a clear solution. A total of 5% bovine serum albumin (BSA) was then added to avoid precipitation. The final concentration of TTA was 1.35 mM. The placebo solution consisted of 0.9% saline water and 5% BSA.

2.4 TTA local delivery
The dissolved TTA was administered at the site of injury using a Transport® multiporous angioplasty balloon catheter. The size of this balloon catheter was selected from the quantitative coronary analysis (QCA) data post-dilatation to assure close apposition of the balloon with the vessel wall. The solution was infused in three bolus doses, each of 0.5 ml, in intervals of 30 s. The catheter has a sleeve embracing the balloon; the solution was delivered through a separate lumen connected to the sleeve that has multiple holes. The inner balloon was expanded to six atmospheres during administration. To eight coronary arteries of four pigs, radiolabelled TTA was administered in order to check the arterial uptake. Two of these pigs were killed after 12 h of radiolabelled TTA local administration, and the other two were sacrificed after 4 weeks of the administration. Isotope measurement and analysis was performed as described elsewhere [16].

2.5 Angiography
Coronary angiography, using ioxaglate (Hexabrix®) as contrast medium, was performed before and after injury and at follow-up from two orthogonal views for QCA. Estimation of the vessel luminal diameter was performed on-line to guide the choice of angioplasty balloon size. The angiographic images were also transferred to a computer for digital storage. QCA was performed after the procedure by analyzing the angiograms on a separate workstation. The guiding catheter served as calibration.

2.6 Intracoronary ultrasound (ICUS)
ICUS was performed to the vessels before and after injury, and at follow-up, 4 weeks later. Lumen area, total vessel area (VA), percent VA stenosis, maximal lumen diameter, minimal lumen diameter, mean lumen diameter and lumen symmetry index were determined by quantitative analysis using a Vingmed 800 echo-machine with a dedicated CVIS system. We used a 10-Hz/3.2 French ICUS catheter. The catheter was advanced over a PTCA-wire distal to injury site. The pullback speed was set to 0.5 mm/s, using an automated pullback device.

2.7 Harvesting
The animals were sacrificed by an overdose of potassium in the aorta. The heart was exposed by left sternotomy and excised. The coronary arteries were then perfusion fixed with buffered 2% glutaraldehyde at a pressure of 100 mmHg for 15 min after flushing with a solution containing Ringer acetate/Xylocaine 1% and Heparin. The side-branches were used to identify the site of injury/local delivery. By using a transport balloon catheter (balloon-length 20 mm) the proximal and distal part of injury/delivery site were marked by needles. The coronary artery between the needles, representing the injury/delivery site, was then excised. All peri-vascular tissue was excised and the artery segment was embedded in paraffin and sectioned for light microscopy and histomorphometry.

Sections (5 –10 µm) were stained with conventional van Giesson to identify the endothelial surface and other components of the vessel wall (Fig. 1). Micrographs were obtained and evaluated quantitatively with respect to lumen area, intimal area/maximal thickness, medial thickness and vessel perimeter/area by computerized planimetry (Leica Q 500 MC, software Q win.01.02).


Figure 1
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  		Fig. 1 Light microscopy of a representative section of the injured minipig coronary artery. L=lumen, I=intima and M=media.

 
2.8 The effect of TTA on copper ion induced LDL oxidation
LDL was prepared from fresh human plasma obtained from five healthy volunteers by sequential ultracentrifugation as described in detail elsewhere [15,17,18]. The oxidation was performed as described earlier [19]. Briefly, 25 µg LDL-protein were placed in 1-ml quartz cuvette to which calcium magnesium free phosphate buffered solution (PBS) at pH 7.4 was added. Different concentrations of TTA were added as specified. The oxidation was initiated by adding freshly prepared copper solution (CuCl2x2H2O) to a final concentration of 10 µM. Oxidation was performed at 37°C in a single-beam UV–Vis recording spectrophotometer (Shimadzu UV-2501 PC), with a capacity of measuring six samples simultaneously. Absorbance was recorded every 2 min up to 3 h. The initial absorbance was set to an arbitrary value and then the increase was recorded over the time period.

2.9 The effect of TTA on activated peripheral blood mononuclear cells (PBMC)
PBMC were isolated from human heparinized plasma obtained from five healthy human donors by Isopaque-Ficoll (Lymphoprep, Nycomed Pharma AS, Oslo, Norway) gradient centrifugation within 1 h after blood sampling as previously described [20]. PBMC were resuspended in RPMI 1640 with 2 mM L-glutamine and 25 mM HEPES buffer (Gibco BRL, Paisley, UK) supplemented with 10% heat inactivated pooled human AB+ serum (culture medium). The endotoxin level in culture medium, reagents and stimulants was <10 pg/ml (quantitative chromogenic limulus amebocyte lysate test, BioWhittaker, Inc., Walkerswille, MD). The release of interleukin (IL)-2 and IL-10 from PBMC was measured as follows: PBMC (106 cells/ml) were incubated in flat-bottomed, 96-well microtiter trays (200 µl/well, Costar, Cambridge, MA) in medium alone or with phytohemagglutinin (PHA) (final dilution 1:100, Murex, Dartford, UK), with or without different concentrations of TTA. BSA was used as a negative control for TTA (vehicle). Cell-free supernatants were harvested after 20 h and analyzed for IL-2 and IL-10 levels by enzyme immunoassays; IL-10 from R&D Systems, Minneapolis, MN, and IL-2 from CLB, Amsterdam, Netherlands. The intra and interassay coefficients of variations were <10% for both assays. All samples from a given individual were analyzed in the same microtiter plate to minimize run to run variability.

2.10 Statistical analysis
Data are presented as mean±standard error of the mean (S.E.M.). Student t-test was used to assess within- and between-group comparisons. The data were analyzed using SPSS for windows 6.0. P-values<0.05 were considered significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 Acknowledgments
 References
 
Follow-up was complete in all 20 pigs and the mean follow-up time was 4 weeks in both placebo and TTA groups. The baseline coronary artery diameter, angioplasty balloon size, and maximal balloon pressures used for creating injury were identical in the two groups. Table 1 shows that radiolabelled TTA was present in the coronary arteries up to 4 weeks. Earlier, we showed that the concentration of TTA in a non-injured segment, distal to the site of application was significantly less than that at the applied site (injured segment) [16].


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  		Table 1 Radiolabelled TTA in delivery and cardiac muscle sites in pigs killed after 12 h and 4 weeks

 
3.1 Angiography
The luminal diameter increased by 13% in the placebo and 23% in the TTA group with no significant difference between the two groups after overstretch injury (Table 2). In contrast, follow up angiography after 4 weeks showed a markedly reduced minimal luminal diameter of the placebo group (1.3±0.1) compared to the TTA group (2.2±0.2 mm), while no differences were found for the reference segment (Table 2). Moreover, the late loss (calculated by subtracting MLD at follow up angiography from that at post dilatation) was significantly larger in the placebo group, and the percent luminal narrowing was 55% in the placebo and 20% in the TTA administered group (P<0.01, Table 2).


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  		Table 2 Angiographic measurements

 
3.2 Histomorphometric analysis
The placebo and TTA treated animals showed no significant differences in neither maximal intimal thickness (0.42±0.04 vs. 0.44±0.05 mm) nor intimal area (0.60±0.06 vs. 0.67±0.09 mm2). Negative remodeling was significantly increased in the placebo comparing the TTA group (Fig. 2). Loss of arterial lumen results from shrinkage of the artery and intimal thickening. Thus, remodeling was defined as the sum of angiographic late loss (negative value) and intimal thickness at follow-up


Figure 2
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  		Fig. 2 The effect of TTA on remodeling of the artery calculated as the sum of the negative value of angiographic late loss and intimal thickness. Data are mean±S.E.M.

 
3.3 Intracoronary ultrasound (ICUS)
The lumen diameter at follow-up, as measured by ICUS, was consistent with angiographic findings showing significant larger both minimal and maximal luminal diameter as well as lumen area in the TTA compared with the placebo group (Table 3).


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  		Table 3 Intravascular ultrasound measurements at maximal stenosis area

 
3.4 Anti-oxidative and anti-inflammatory effects of TTA
We examined if TTA could impair the copper induced oxidation of LDL (see Section 2). As shown in Fig. 3, TTA increased the lag time prior to the oxidation in a dose-dependent manner. In contrast, Palmitic acid, which was used as a control, had no significant effect on the oxidative modification of LDL.


Figure 3
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  		Fig. 3 Effect of TTA on in vitro copper induced LDL oxidation, diene absorbance at 234 nm. ({circ}) 5 µM Palmitic acid, ({bigtriangleup}) Blank (No Addition), ({square}) 5 µM TTA, ({blacksquare}) 10 µM TTA, ({blacktriangleup}) 15 µM TTA, (x) 20 µM TTA. Data shown are from one representative experiment.

 
To elucidate any potential anti-inflammatory effects of TTA we examined the effect of TTA on PHA stimulated cytokine levels in PBMC supernatants (see Section 2). Fig. 4A shows that TTA markedly decreased the level of the inflammatory cytokine IL-2 ({approx}65%) in these cells in a dose-dependent manner. Concomitantly, TTA induced a marked increase in the PHA stimulated level of the anti-inflammatory cytokine IL-10 ({approx}10-fold increase, Fig. 4B), possibly resulting in a strong anti-inflammatory net effect. Similar pattern was found when the cytokine levels were expressed as concentration per number PBMC (data not shown). In contrast, no significant effect on levels of these cytokines was seen when BSA (TTA vehicle) was added to PHA stimulated PBMC (Fig. 4).


Figure 4
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  		Fig. 4 The effect of different concentrations of TTA on the release of IL-2 (A), IL-10 (B) in PBMC supernatants from five healthy blood donors incubated with PHA (final dilution 1:100). For comparison the effects of BSA (vehicle) are also shown. ({blacksquare}) Blank, ({image}) BSA and ({square}) TTA. *P<0.01 vs. PHA without TTA. Data are mean±S.E.M.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
Acknowledgments
 References
 
Stenosis development after injury and restenosis after angioplasty may be induced by inflammatory responses to injury, possibly involving the formation of oxidative stress. In the present study, we report for the first time that TTA can markedly impair the formation of stenosis in coronary arteries after PTCA in minipigs as assessed by both angiographic, histomorphometric and ICUS examination. Moreover, our findings, demonstrating marked antioxidant and anti-inflammatory effects of TTA, further support the notion that inflammation and oxidative stress may be involved in the pathogenesis of restenosis in coronary arteries [21]. By interacting with each other [21], these processes (i.e. inflammation and oxidative stress) may represent a vicious circle operating in the pathogenesis of restenosis of coronary arteries that may be inhibited by TTA.

TTA has many chemical and physical properties in common with normal saturated fatty acids, but it can not undergo β-oxidation [22]. This sulfur substituted fatty acid analogue, however, can be metabolized in the liver by extra mitochondrial {omega}-oxidation and sulfur-oxidation followed by peroxisomal β-oxidation to short sulfoxy dicarboxylic acids, which then are excreted via the kidneys [23]. Primary toxicological studies in two different species (rat and dogs) and various cells have shown no toxic effects of TTA. In addition, it was shown that TTA is not mutagenic. Preliminary studies on hypertensive rats, we have observed a reduced blood pressure after TTA administration (data to be published).

The radioactivity that was found in the arterial wall (Table 1 and previously reported [16]) is most probably due to TTA itself and not a TTA-metabolite or the {Delta}9-desaturated form that was recently found in TTA treated rats [24]. Evidence for this arises from the knowledge that the heart and arteries have low {omega}-hydroxylation and mono-oxygenase activities [25]. Moreover, phospholipids are the main lipid class that is found in the arterial wall, and notably, TTA is mostly found incorporated into phospholipids after administration to rats [24] possibly also explaining why TTA was retained in the arterial wall. Thus, TTA may be a promising substance for local drug delivery as a sustainable tissue concentration can be obtained over a long time period.

After the initial vessel recoil, it has been observed that restenosis is primarily caused by arterial remodeling, but also intimal thickening due to smooth muscle proliferation and migration from the media of the vessel wall appears to be involved [26–28]. Our data suggest that TTA affects stenosis after balloon angioplasty through its effect on remodeling. An effect of TTA on smooth muscle proliferation has previously been demonstrated in vitro [29]. However, no inhibitory effect of TTA on intimal thickening was detected in this study. A possible reason for that could be low TTA concentration in the intima. TTA delivery via a transport catheter could result in a purely adventitial localization of the compound, which might explain the favorable inhibitory effect on constrictive remodeling.

It has been reported that oxidative stress stimulates collagen type I gene expression and consequently increases collagen production in human fibroblasts [30,31].

Taken together, it seems plausible that TTA delivered via a transport catheter results in adventitial localization, where it can exert its antioxidant effect resulting in an inhibitory effect on collagen production and constrictive remodeling. Further studies are in progress to clarify any direct effect of TTA on the biology of the arterial wall.

In the present study, we report potent antioxidant effects of TTA (Fig. 3 and previously reported [15]), possibly involving metal ion binding and free radical scavenging [15]. It is noteworthy that the antioxidant properties of TTA might be different from those of vitamin E [15], which in addition to low local tissue concentration comparing TTA, may explain why naturally occurring vitamins have been less successful in reducing stenosis after balloon injury [9,32].

In addition to antioxidant effects, we also report the potent anti-inflammatory effect of TTA, not only by suppressing the level of the inflammatory cytokine IL-2, but also by markedly enhancing the levels of the anti-inflammatory cytokine IL-10. While the suppressive effect on IL-2 level may involve reduced oxidative stress [33], oxidative stress seems not to be involved in the regulation of IL-10. These combined effects of TTA on oxidative stress and inflammation and especially the markedly enhancing effect on IL-10 levels may be of particular importance. Hence, IL-10 which is a powerful deactivator of macrophages and T cells [34,35], has been found to have protective effects on the development of atherosclerosis and viral myocarditis in mice [36]. Moreover, IL-10 was also recently found to inhibit intimal hyperplasia after angioplasty or stent implantation in hypercholesterolemic rabbits [37]. Nevertheless, TTA appears to preferentially affect remodeling rather than intimal thickening. This might be mediated through TTA’s effect on interleukins (IL-2 and IL-10) (Fig. 4), which in turn might modulate matrix metalloproteinases (MMPs) and growth factors such as basic fibroblast growth factor (bFGF) [38,39]. Both IL-2 and IL-10 have been reported to influence MMPs and bFGF [40–42].

Both cell proliferation, apoptosis as well as inflammation are supposed to play a role in restenosis after angioplasty, and modulation of these processes through ligands of the PPAR may represent a novel recent approach in restenosis therapy. Earlier, it has been shown that TTA is a potent activator of PPAR{alpha} and PPAR{gamma} [12]. This activation may also be of importance for the anti-inflammatory effects of TTA. Notably, PPAR{alpha} and PPAR{gamma} have been shown to be activated by anti-inflammatory drugs [43], and PPAR agonists may inhibit production of inflammatory cytokines in monocyte [44]. Whether the anti-inflammatory effect of TTA is mediated via the PPAR or independent of it needs to be clarified.

In conclusion, TTA may be promising substance for local drug delivery and a potent inhibitor of restenosis in coronary arteries. This effect on restenosis seems to involve both antioxidant and anti-inflammatory mechanisms.

Time for primary review 21 days.


   Acknowledgments
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
References
 
This work was supported by a grant from the Bergen Heart Foundation, the University of Bergen and Norwegian Council on Cardiovascular disease, Norway. The authors are grateful to Mrs Kari Williams for excellent technical assistance.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 

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