Christian Beythien

Effects of gold coating of coronary stents on neointimal proliferation following stent implantation

Experimental studies suggest a reduced neointimal tissue proliferation in vascular stainless steel stents coated with gold. This prospective multicenter trial evaluated the impact of gold coating on neointimal tissue proliferation in patients undergoing elective stent implantation. The primary end point was the in-stent tissue proliferation measured by intravascular ultrasound at 6 months comparing stents of identical design with or without gold coating (Inflow). Two hundred four patients were randomized to receive uncoated (group A, n = 101) or coated (group B, n = 103) stents. Baseline parameters did not differ between the groups. Stent length and balloon size were comparable, whereas inflation pressure was slightly higher in group A (14 +/- 3 vs 13 +/- 3 atm, p = 0.013). Procedural success was similar (A, 97%; B, 96%). The acute angiographic result was better for group B (remaining stenosis 4 +/- 12% vs 10 +/- 11%, p = 0.002). Six-month examinations revealed more neointimal proliferation in group B. By ultrasound, the neointimal volume within the stent was 47 +/- 25 versus 41 +/- 23 mm(3) (p = 0.04), with a ratio of neointimal volume-to-stent volume of 0.45 +/- 0.12 versus 0.40 +/- 0.12 (p = 0.003). The angiographic minimal luminal diameter was smaller in group B (1.47 +/- 0.57 vs 1.69 +/- 0.70 mm, p = 0.04), with a higher late luminal loss of 1.17 +/- 0.51 versus 0.82 +/- 0.56 mm (p = 0.001). Thus, gold coating of the tested stent type resulted in more neointimal tissue proliferation.

Relation of Stent Design and Stent Surface Material to Subsequent In-Stent Intimal Hyperplasia in Coronary Arteries Determined by Intravascular Ultrasound

A variety of different stent designs and coatings have become available. This study sought to determine the impact of stent design and gold-coating of stents on intimal hyperplasia (IH) in human atherosclerotic coronary arteries in relation to known predictors of restenosis. Angiographic and intravascular ultrasound (IVUS) studies were performed at 6-month follow-up on 311 native coronary lesions of 311 patients treated with 99 Multi-Link stents, 74 InFlow steel stents, 73 InFlow gold-coated stents, 41 Palmaz-Schatz stents, 12 NIR steel stents, and 12 gold-coated NIR Royal stents. Lumen and stent cross-sectional area (CSA) were measured at 1-mm axial increments. Mean IH CSA (stent CSA - lumen CSA) and mean IH thickness were calculated and averaged over the total stent length. IVUS demonstrated different levels of IH for the 6 stents. Mean IH thickness ranged from 0.20 +/- 0.13 mm for Multi-Link stents to 0.43 +/- 0.14 mm for InFlow goal-coated stents (p <0.001). Multivariate analysis proved non-Multi-Link stent design (odds ratio 3.45, 95% confidence intervals 1.13 to 11.11, p <0.034) and gold coating (odds ratio 3.78, 95% confidence intervals 1.88 to 7.54, p <0.001) to be the only independent predictors of IH thickness >0.3 mm. In conclusion, stent design and surface material have an important impact on the IH response to stents implanted in human coronary arteries. However, the differences in IH thickness between the analyzed stents were relatively small compared with the absolute lumen dimensions.

Sulfatides Activate Platelets Through P-Selectin and Enhance Platelet and Platelet–Leukocyte Aggregation

Objective— Sulfatides are sulfated glycosphingolipids present on the surface of a variety of cells; however, their exact physiological function is not known. Recently, we have shown that the inhibition of sulfatide–P-selectin interactions leads to disaggregation of platelet aggregates. Methods and Results— In this study, we show that sulfatides activated platelets as they increased activation of GPIIb/IIIa (PAC-1 epitope) and expression of P-selectin on the platelet surface. Furthermore, sulfatides aggregated washed platelets in a dose-dependent manner and enhanced platelet aggregation in platelet-rich plasma. Previous activation of platelets was necessary for this effect. Monoclonal anti–P-selectin antibodies inhibited not only sulfatide-induced PAC-1 binding to platelets but also sulfatide-induced platelet aggregation, suggesting that sulfatides activate platelet GPIIb/IIIa via signaling through P-selectin. The proaggegatory effect of sulfatides was also observed in an ex vivo thrombosis model using whole blood and pulsatile flow at 37°C. In this model, sulfatides significantly enhanced platelet aggregation and the formation of platelet–leukocyte aggregates. Conclusions— We show that sulfatide-P-selectin interactions lead to subsequent platelet activation and P-selectin expression, forming a positive feedback loop that can potentiate formation of stable platelet aggregates. In addition, sulfatides enhance the aggregation of platelet–leukocyte aggregates. These mechanisms may play a significant role in hemostasis and thrombosis.

Flow cytometric analysis of coronary stent-induced alterations of platelet antigens in an in vitro model

One of the limitations of coronary stenting is the subacute thrombotic occlusion. In an in vitro model, we examined the effects of tantalum wire stents (n = 12) on platelet antigens. Platelet-rich plasma (PRP) was circulated in PVC tubing systems. At fixed intervals over a 10-min time course, aliquots of PRP were drawn, stained with monoclonal antibodies (CD41a, CD42b, CD62p, and CD63), and analyzed by flow cytometry. Within 2 minutes of the onset of circulation, expression of the activation-dependent antigens CD62p and CD63 increased in all tubing systems with stents. This early increase was followed by a progressive rise in fluorescence intensity of these neoantigens over the course of 10 minutes (p < 0.05 vs.. control system without stent). Antigens CD41a and CD42b did not show significant changes in either system. The artificial surfaces and shear forces of stent meshes induce alterations in platelet antigens. Flow cytometry provides a sensitive technique for in vitro testing of the thrombogenicity of coronary stents, and may be useful in further improving stent biocompatibility.

In vitro model to test the thrombogenicity of coronary stents

Thrombotic occlusion is a major complication limiting the application of stents in coronary arteries. In an in vitro model we investigated the thrombogenicity of different stent materials and several medical regimens to prevent thrombotic occlusion. Experiments were conducted in a closed system of silicon tubing with circulating citrated platelet rich plasma of healthy volunteers (n = 7) and of patients (n = 7 for each condition). Patients were either treated with phenprocoumon or with high or low dose heparin in combination with aspirin alone (100 mg) or aspirin (990 mg) plus dipyridamole (225 mg). After placement of tantalum wire stents into the system platelet aggregates were visible after 13.5 +/- 3.0 min, and occlusion occurred after 15.0 +/- 3.5 min. Similarly, with implanted stainless steel stents aggregation was seen after 13.0 +/- 3.5 min and thrombosis occurred after 14.5 +/- 3.5 min (p < 0.001 vs control without stent). Microscopic examination revealed combined platelet fibrin thrombi occluding the lumen. Platelet components predominately covered stent wires, particularly at crossing points. In all experiments high-dose heparin prevented platelet aggregate formation and stent occlusion independently of additional aspirin or aspirin plus dipyridamole; perfusion time > 60 min (p < 0.001 vs no heparin). Low-dose heparin could not prevent clotting. With aspirin alone aggregates were visible after 16.0 +/- 4.0 min and clotting occurred after 23.0 +/- 5.0 min. In combination with dipyridamole aggregates were visible after 15.5 +/- 5.0 min and clotting after 21.0 +/- 4.0 min (NS vs aspirin alone). Phenprocoumon prevented platelet aggregate formation and stent occlusion; perfusion time > 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Stent Length and Heparin Coating on Platelet Activation: A Flow Cytometric Analysis in a Pulsed Floating Model

Platelets are involved in acute and subacute thrombotic occlusions of coronary stents and also may play a role in the pathophysiology of in-stent restenosis. This study sought to investigate the expression of activation dependent glycoproteins on platelets by flow cytometry and time until stent thrombosis in an in vitro model of stent thrombosis. Coronary stents were placed in parallel silicon tubings with circulating citrated platelet rich plasma to measure 1) influence of stent length on platelet antigens; 2) influence of heparin coating on platelet antigens; and 3) time until stent thrombosis. After recalcification aliquots of platelet-rich plasma were taken over 10 minutes in 2-minute intervals and immediately fixed and stabilized. For flow cytometric analysis monoclonal antibodies to CD41a (glycoprotein IIb/ IIIa), CD42b (glycoprotein Ib-V-IX), CD62p (P-selectin), and CD63 (glycoprotein 53) were used. Within 2 minutes after start of circulation, the expression of CD62p and CD63 increased. Longer stents resulted in more platelet activation than shorter stents (25 mm vs. 15 mm; p<0.001. Time until stent thrombosis was reduced (25 mm vs. 15 mm; p<0.05). Heparin coating did not significantly influence flow cytometry detectable platelet activation but prolonged time until stent thrombosis (coated vs. uncoated; p<0.005). In control tubing systems without stents platelet activation was less pronounced (p<0.0001). Antibodies to CD41a and CD42b did not show significant changes. In this model platelet activation detected by flow cytometry and time until stent thrombosis were dependent on stent length and coating. In vitro testing could be useful to optimize stent design and material.

Platelet Hemostasis Capacity in Smokers: In Vitro Function Analyses with 3.2% Citrated Whole Blood

INTRODUCTION Platelet function may be influenced by cigarette smoking. We therefore examined the effect of smoking on platelet hemostasis capacity (PHC) with an in vitro analyzer (PFA-100). METHODS AND RESULTS Healthy blood donors (n=54) were included in the study and divided into four groups: nonsmoking males (n=14), nonsmoking females (n=14), smoking males (n=12) and smoking females (n=14). For in vitro analyses, in each participant citrated blood (3.2% buffered) was tested for PHC by two cartridges coated with collagen, and additionally with epinephrine (Col/Epi) or ADP (Col/ADP). Analyses were performed within 4 h after sample taking. PHC was expressed as the time in seconds to occlude the cartridge (closure time, CT). The average CT was significantly prolonged in female smokers compared to the female nonsmoking group for both types of cartridges (Col/Epi: P=.02; Col/ADP: P=.03). No significant differences were detected comparing the CT of smoking and nonsmoking males. After pooling male and female smokers and nonsmokers, no significant differences could be found, neither for the Col/Epi cartridges nor the Col/ADP cartridges. Plaletet aggregation assays performed in parallel showed no significant differences, except a reduced aggregability in male smokers compared to male nonsmokers using epinephrine 8.0 microM/ml as activating agent (P=.01). Furthermore, smoking volunteers presented with a significantly increased fibrinogen level compared to nonsmoking volunteers (P<.01). CONCLUSIONS The results of our study show that in habitual smokers PHC (PFA-100) and the capability of platelets to react upon agonist stimulation in aggregation assays is not significantly influenced or increased compared to healthy nonsmokers. However, an immediate effect of cigarette smoking cannot be excluded.

Value of Intravascular Ultrasound for Endovascular Stent‐Graft Placement in Aortic Dissection and Aneurysm

Abstract  Background: Endovascular stent‐graft placement is a new concept for the treatment of aortic dissection and aneurysm. Intravascular ultrasound (IVUS) with established diagnostic features may be instrumental in guiding endovascular procedures. Methods: We performed IVUS and digital angiography before, during, and after implantation of 47 stent grafts in 40 patients with Stanford type B dissection (26 patients, 28 stent grafts), thoracic aneurysm (9 patients, 11 stent grafts), and abdominal aneurysm (5 patients, 8 stent grafts). Results: IVUS could clearly identify the aortic anatomy and differentiate between true and false lumen in all cases of dissection. In four patients with type B dissection extending from the thoracic to the abdominal aorta the true lumen was exclusively identified by IVUS, and thus, essential for safe execution of the procedure. In another patient stent‐graft placement in the aorta was optimized by covering a second entry detected by IVUS, but undetected by angiography. The site of stent implantation, the true and false lumen, as well as entry and reentry were always identified in both thoracic and abdominal aorta. In comparison with angiography, IVUS information led to additional balloon molding due to incomplete stent apposition in seven cases. Conclusions: As an adjunctive imaging modality IVUS is likely to improve stent‐graft placement in aortic type B dissection, especially in patients with abdominal extension.

Multicenter evaluation of the Strecker tantalum stent for acute coronary occlusion after angioplasty

The Strecker stent is a balloon-expandable, flexible endoprosthesis constructed of knitted tantalum wire and has been implanted successfully in peripheral arteries. This study presents the first multicenter experience with implantation of this radiopaque device in the coronary arteries in 64 patients of 6591 consecutive percutaneous transluminal coronary balloon angioplasty (PTCA) procedures complicated by abrupt closure. In all except 1 patient the stents (n = 72) were correctly placed, and flow could be reestablished immediately. During hospitalization 12 (19%) patients had stent closures; 5 (8%) patients had Q-wave myocardial infarctions; and 13 (20%) patients underwent bypass surgery (4 on an emergency basis). The in-hospital mortality was 9%: 2 patients died after thrombotic stent occlusions; 2 patients had fatal bleeding complications; and 2 patients died after bypass surgery. Major bleeding complications at the puncture site were observed in 8 (12.5%) patients. Angiograms (n = 45) after 17 +/- 5 weeks revealed a stent patency rate of 89%. Thus the Strecker coronary stent proved to be helpful in the management of acute vessel closure during PTCA. However, in this first series a high incidence of early thrombotic occlusions and bleeding complications warrants close anticoagulation monitoring and limits broader indications.

Influence of heparin coating of coronary stents and ex vivo efficacy of different doses of acetylsalicylic acid and ticlopidine in a pulsed floating model of recirculating human plasma

Acute occlusion of stented coronary vessels still occurs in up to 3%. Acitvated platelets have been found to play a major role in the pathogenesis of these complications. We therefore analyzed the efficacy of a heparin coating of coronary stents and investigated the ex vivo efficacy of different antiplatelet drugs. Each of seven healthy volunteers was treated with each of the following medications for 7 days: ASA 100 mg/day, ASA 300 mg/day, ticlopidine 250 mg/day, and ticlopidine 500 mg/day. Three standardized in vitro silicon tubing models, one of them containing an uncoated stent, one a heparin-coated stent, and one without a stent (control) were filled with PRP and circulation was started. TOS in systems with heparin-coated stents was 2.4-times longer compared to systems with uncoated stents ( P <0.001), and 1.5-times longer compared to the control ( P <0.01). The increase of CD62p expression within the first 5 min was 2.5-times higher in systems with uncoated stents and 1.7-times higher in the control than in systems with heparin-coated stents ( P <0.05). Aggregometry revealed significant medication- and dose-dependent inhibition of platelet aggregability for all medications. Heparin-coating of coronary stents reduces their thrombogenicity significantly. ASA and ticlopidine effectively reduce platelet activation ex vivo . The used in vitro system facilitates a reproducible method to estimate the thrombogenicity of coronary stents prior to in vivo trials.