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(Circulation. 1997;95:1549-1553.)
© 1997 American Heart Association, Inc.

Articles

Experimental Study of Thrombogenicity and Foreign Body Reaction Induced by Heparin-Coated Coronary Stents

Ivan De Scheerder, MD, PhD; Kai Wang, MD; Krzysztof Wilczek, MD; Dirk Meuleman, PhD; Ronald Van Amsterdam, PhD; Gerard Vogel, BS; Jan Piessens, MD, PhD; Frans Van de Werf, MD, PhD

From the Department of Cardiology (I.D.S., K. Wang, K. Wilczek, J.P., F.V.D.W.), Gasthuisberg, University Hospital, Leuven, Belgium; and Department of Vascular Pharmacology (D.M., R.V.A., G.V.), Organon International BV, Oss, The Netherlands.

Correspondence to I. De Scheerder, MD, PhD, Gasthuisberg University Hospital, Department of Cardiology, Herestraat 49, 3000 Leuven, Belgium.

	Abstract

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Background Results of recent randomized clinical trials have revealed a significant reduction in angiographic restenosis rate when adjunctive stenting was performed after conventional coronary balloon angioplasty. The thrombogenicity of metal stents, however, remains a concern. In the present study, we compare the thrombogenicity of heparin-coated coronary stents with that of bare metallic coronary stents.

Methods and Results Thrombogenicity of metallic coronary stents (four heparin-coated and eight bare stents) was studied in a rat arteriovenous shunt model with the use of ¹²⁵I-labeled fibrinogen and ⁵¹Cr-labeled platelets. Total clot weight after 30-minute follow-up was significantly lower in the heparin-coated stents compared with the bare stents (8.1±3.7 versus 25.8±4.6 mg; P<.001). Relative ¹²⁵I and ⁵¹Cr activities in the stents were significantly higher in the bare stents than in the heparin-coated stents (¹²⁵I, 1.03±0.43 versus 0.18±0.04, P=.003; ⁵¹Cr, 17.5±6.8 versus 4.4±1.0, P=.004). Subsequently, heparin-coated and bare stents were randomly implanted in the right coronary artery of 20 domestic pigs. Angiographic parameters were similar between both groups at baseline and after 6-week follow-up. Morphometry also did not show a significant difference in lumen area (bare, 1.03±0.83 mm²; heparin-coated, 1.12±0.73 mm²; P=NS) or neointimal hyperplasia (bare, 1.01±0.81 mm²; heparin-coated, 1.21±0.57 mm²; P=NS).

Conclusions Heparin coating of metallic coronary stents decreases their thrombogenicity but does not improve late vessel patency and neointimal hyperplasia at follow-up in a porcine coronary model.

Key Words: stents • heparin • thrombus • stenosis

	Introduction

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Metallic coronary stents exert a continuous radial pressure on the diseased coronary artery, resulting in compression of atherosclerotic plaques, sealing of dissections, and expansion of the coronary vessel.^{1 2} When used as an adjunct to conventional balloon angioplasty, the stents improve vessel patency.^{3 4}

Early clinical experience revealed frequent thrombotic stent closure and abundant healing response, resulting in a more pronounced neointimal hyperplasia compared with conventional balloon angioplasty.^{2 3 4 5 6} Optimal stent implantation and the use of antiplatelet treatment instead of full anticoagulation significantly decreased thrombotic complications after stent implantation.

Recently, heparin-coated stents were clinically introduced to further decrease in-hospital complications. In the present study, we compare the thrombogenicity of heparin-coated stents with that of bare metallic stents. Furthermore, we evaluate the potential beneficial effect of heparin coating on the increased hyperplastic response to the implanted metallic stent.

	Methods

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Materials
Self-designed balloon-expandable stainless steel stents were made of 0.18-mm stainless steel wire, folded in a zig-zag shape over a 6F tubular device. These stents can easily be mounted onto any conventional angioplasty balloon and deployed with a minimal pressure of 6 atm.^{7 8}

For the present animal experiments, the stents were coated with Duraflo II heparin (Bentley, Baxter Healthcare Corp).

The Duraflo II coating consists of unfractionated USP heparin and a hydrophobic binding agent. The binding agent is incorporated into the structure of heparin in such a way that the modification affects the physicochemical but not the biological properties of heparin. A submicronic layer of coating was applied to all surfaces of the stent.^{9 10 11}

Stent Thrombogenicity in a Rat Arteriovenous Shunt Model
Heparin-coated (n=4) and bare stainless steel (n=8) stents were deployed in an arteriovenous shunt (internal diameter, 2.0 mm) that was connected between the left carotid artery and the right jugular vein of male Wistar Hsd/Cpb rats (body weight, 300 to 340 g). The thrombogenicity of the stents was considered to be related to the radioactivity measured in the inserted cannula after systemic administration of ¹²⁵I-labeled fibrinogen and ⁵¹Cr-labeled platelets.

After the rats were anesthetized with sodium pentobarbital (60 mg/kg IP), the left carotid artery and the right jugular vein were exposed from the surrounding tissue. The prepared arteriovenous shunt, which was filled with saline, was inserted into the jugular vein and the opposite carotid artery, after which blood circulation via the shunt was started. The segment of the shunt containing the stent was positioned between two detectors that continuously measured the radioactivity of the ⁵¹Cr-labeled platelets and ¹²⁵I-labeled fibrinogen. Blood circulation was monitored by the continuous measurement of the blood flow according to the Doppler flow technique. Blood circulation was allowed for 30 minutes, during which none of the cannulas occluded. Continuous measurements of ⁵¹Cr-labeled platelets and ¹²⁵I-labeled fibrinogen deposition were obtained using the Mumed automated isotope measuring system. At the end of the experiment, the thrombus, removed from the shunt, was characterized by weight and by its ⁵¹Cr-labeled platelet and ¹²⁵I-labeled fibrinogen content. The latter two parameters were measured as the ratio of radioactivity of the clot to the radioactivity of the blood before insertion of the arteriovenous shunt.

Labeling of fibrinogen was performed according to the lactoperoxidase method described by Marchalonis.¹² Clottable human fibrinogen (Kabi), 10 to 15 µg per rat, was labeled with 18.5 MBq of I-125 NEZ-033a (E.I. Dupont de Nemours GmBH) and stored in fractions of 150 µL each at -70°C until use to obtain 0.04 to 0.06 MBq for each rat at the day of injection. On the day of the experiment, 1 mL of saline was added to one fraction of ¹²⁵I-labeled fibrinogen, after which 0.1 mL per rat was injected before insertion of the arteriovenous shunt.

Labeling of platelets was performed according to the method described by Meuleman et al.¹³ On the day before the experiment, platelets were harvested from donor rats (one donor for two acceptor rats) and labeled with [⁵¹Cr]Na₂CrO₄ (Amersham), 0.9 to 1.7 x 10⁹ platelets, corresponding to 0.4 to 0.8 MBq of ⁵¹Cr. Labeling efficiency was 50%. Recovery after 1.5 hours of blood circulation in the rat was 80% to 100%.

Stent Thrombogenicity and Neointimal Response in a Porcine Coronary Model
Stent implantation in the right coronary artery of domestic crossbred pigs was performed according to the method described by De Scheerder et al.^{14 15}

In the first series of experiments, the presence of mural thrombi was studied 7 days after stent implantation. Either a heparin-coated or a bare stent was randomly placed in the right coronary artery of 20 pigs. At 7-day follow-up, quantitative coronary angiography was performed. The pigs were killed with an intravenous bolus of 10 mL of oversaturated potassium chloride. The right coronary artery was harvested for visual inspection of the stent.

In a second series of 20 experiments, the degree of foreign body reaction that occurred at 6 weeks after stent implantation was studied. Either a heparin-coated or a bare stent was randomly deployed in the right coronary artery of 20 pigs. At 6-week follow-up, final angiograms were obtained. The pigs were killed, and the right coronary artery was harvested for histopathology and morphometry. For these late follow-up studies, instrumentation of the pigs and angiographic techniques were identical to those used during the implantation procedure with the exception of intubation with a tracheotomy.

Measurements
Quantitative Coronary Angiography
Angiographic analysis of stented vessel segments was performed before and immediately after stenting and at follow-up with the Polytron 1000 system. The Polytron 1000 system was previously validated in vitro and in vivo^{16 17 18} with a metal bar as a calibration device.¹⁹ The diameter of the stented vessel segments was measured. The degree of oversizing was expressed as the ratio of balloon to artery thickness.

Histopathology and Morphometry
After the 6-week follow-up, the pigs were killed, and the stented coronary segments were carefully dissected together with a 1-cm minimum vessel segment both proximal and distal to the stent. The segment was fixated in a 2% formalin solution. The stent filaments were removed with the use of a stereomicroscope to avoid distortion of or damage to the artery. Sections from each arterial segment were stained with hematoxylin and eosin, van Gieson's elastic, phosphotungstic acid hematoxylin, and Masson's trichrome stains. Light microscopic examination was performed by an experienced pathologist who was blinded to whether coating was applied. Morphometric analysis of the coronary segments harvested was performed with the use of morphometry software (Leitz CBA 8000). Measurements of maximal intimal thickening and of the areas within the lumen (lumen area) and inside the internal elastic lamina (intimal area) were performed on the arterial sites, being visually appreciated as the most proliferative.

Statistical Analysis
Thrombogenicity of the heparin-coated and bare stents was compared with the use of unpaired Student's t tests. Thrombotic events after stent implantation were compared with the use of a ² test. Arteriographic measurements before, immediately after, and 6 weeks after stent implantation were compared using paired Student's t tests. Comparison of both study groups was performed using unpaired Student's t tests. Data are presented as mean±SD. A value of P<.05 was considered statistically significant.

	Results

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Stent Thrombogenicity in the Rat Carotid Arteriovenous Shunt Model
After 30 minutes, the total clot weight in the bare stents was significantly higher than that in the heparin-coated stents. Similarly, many more radioactive ¹²⁵I-labeled fibrinogen and ⁵¹Cr-labeled platelets were measured in the bare stents (Table 1 and Figs 1 and 2).

View this table: [in this window] [in a new window]   Table 1. Comparison of Thrombogenicity of Heparin-Coated and Bare Stainless Steel Stents Tested in Rat Arteriovenous Shunt Model

View larger version (24K): [in this window] [in a new window]   Figure 1. Continuous measurements of 51Cr-labeled platelet deposition on the stented arteriovenous shunt over 30 minutes showing a comparison between the heparin-coated and the control (bare) stents.

View larger version (25K): [in this window] [in a new window]   Figure 2. Continuous measurements of 125I-labeled fibrinogen deposition on the stented arteriovenous shunt over 30 minutes showing a comparison between the heparin-coated and the control (bare) stents.

Stent Thrombogenicity in Porcine Coronary Arteries
A total of 10 heparin-coated and 10 bare stents were randomly implanted in the right coronary artery of 20 pigs. The angiographic measurements obtained in the stents before, immediately after, and at 7 days after implantation are presented in Table 2; no significant differences between stent types were observed. However, after the animals were killed, visual inspection of the stents revealed mural thrombi in 8 bare stents but only 2 heparin-coated stents (P<.02).

View this table: [in this window] [in a new window]   Table 2. Quantitative Coronary Angiographic Analysis of Stented Vessel Segments at 7-d Follow-up

Foreign Body Reaction Provoked by Stent Implantation in Porcine Coronary Arteries
In a second series of experiments, a total of 10 heparin-coated and 10 bare stents were again randomly implanted in the right coronary artery of 20 pigs. There were no significant differences in the angiographic measurements obtained before, immediately after, and at 6 weeks after stent implantation (Table 3). Similarly, the postmortem morphometric analysis showed no difference in the different transversal areas measured at the most reactive intrastent site (Table 4). Phosphotungstic acid hematoxylin staining was positive in 9 of the bare metallic stents compared with 2 of the heparin-coated stents (P<.002).

View this table: [in this window] [in a new window]   Table 3. Quantitative Coronary Angiographic Analysis of Stented Vessel Segments at 6-wk Follow-up

View this table: [in this window] [in a new window]   Table 4. Morphometry Performed 6 wk After Porcine Right Coronary Artery Stenting

	Discussion

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The present study shows that metallic stents that are heparin coated result in fewer thrombotic phenomena at the implantation site.

When a heparin-coated stent was implanted in a shunt connecting the carotid artery and jugular vein of Wistar rats, less clot formation was found than after implantation of a bare metallic stent. This observation was reflected in reduced accumulation of radioactive fibrinogen and platelets and a smaller thrombus. Subsequently, when the stents were implanted in normal porcine right coronary arteries, after 7 days, mural thrombi were found in eight bare metallic stents but only two heparin-coated stents (Fig 3). These results are concordant with the data recently published by Hårdhammar et al,²⁰ who used another type of heparin coating and demonstrated a significant decrease in subacute thrombotic occlusions in the heparin-coated stents.

View larger version (152K): [in this window] [in a new window]   Figure 3. Photomicrograph of a stented portion of a vessel. In this case, a bare (noncoated) stent was used. Note the thrombus formation surrounding the stent filament sites (hematoxylin and eosin stain; magnification, x40).

These observations are clinically relevant. Early clinical experience with coronary stents was hampered by early thrombotic stent occlusion resulting in an unacceptable morbidity and even mortality. Optimal stent implantation with intravascular ultrasound and/or high-pressure stent deployment²¹ and the use of antiplatelet treatment^{22 23} instead of full anticoagulation significantly decreased this dramatic complication. High-pressure stent deployment, however, can be complicated by distal dissection and increased vessel injury resulting in a more pronounced neointimal hyperplasia,²⁴ and the use of ticlopidine may be limited by systemic hematological side effects. Therefore, heparin-coated stents could represent an attractive alternative, especially in small vessels and more diffuse coronary disease, in which multiple stents or single long stents are needed.

Our longer-term experiments show that after 6 weeks, no difference was present between the intrastent diameters of the heparin-coated and bare stents, as measured either angiographically or morphometrically. This finding may be surprising because earlier experimental studies suggest that platelets, thrombin, and mural thrombosis are involved in the restenosis process.^{25 26} Fig 3 shows an example of mural thrombi formation surrounding the stent filaments. Fig 4 shows an organized mural thrombus at 6-week follow-up, suggesting the important role that organization of mural thrombi might play in the restenosis process. Our results are concordant with the results of Hårdhammar et al.²⁰ They demonstrated a significantly thicker neointima in the heparin-coated stent group compared with the bare stent group after 4-week follow-up. This difference, however, became insignificant after 12-week follow-up. These findings open the debate on the real importance of platelet adhesion and mural thrombi formation on neointimal hyperplasia after stent implantation. After balloon angioplasty, organization of mural thrombi seems to play a major role in the restenosis process. This study suggests, however, that this is less so after stent implantation. Other factors, such as deep injury caused by the deployment of the stent in the diseased artery and a foreign body response caused by the implantation of a foreign body, are potentially more important in the pathogenesis of neointimal hyperplasia after stent implantation.

View larger version (142K): [in this window] [in a new window]   Figure 4. Photomicrograph of a stented part of the vessel 6 weeks after implantation of a bare (noncoated) stent showing an organized mural thrombus. Phosphotungstic acid hematoxylin staining shows the remaining fibrin in this organized thrombus (magnification, x400).

Conclusions
This study demonstrates that heparin coating of metal coronary stents reduces their thrombogenicity but does not influence the neointimal hyperplasia.

	Acknowledgments

 
The authors thank Lisa Tam for coating the stents, Tony Stassen for excellent technical assistance, and Joke Tack and An Makowski for excellent secretarial assistance in preparation of the manuscript.

Received July 23, 1996; revision received October 14, 1996; accepted November 4, 1996.

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