Vascular response after implantation of coated and non-coated coronary stents

The aim of this thesis was to study vascular response to coronary interventions. This involved study of vessel wall injury, both acute and chronic, endothelial dysfunction and the performance of drug-eluting stents in clinical practice, as they are associated with delayed vascular healing due to their anti-proliferative capacity. The first part of the thesis is focussing on the vascular wall trauma, caused by the interventions. Chapter 2 describes the four phases of wound healing after intracoronary stenting, i.e. the early thrombotic response, followed by the recruitment phase with cellular infiltration, the proliferative phase and the final healing phase. In chapter 3 it is shown that the vessel wall injury inflicted in the acute phase by stenting is even increasing in the weeks after the intervention. Two very different stent types were studied in the porcine coronary model and the difference in response suggests that persistent inflammatory response and stent design may influence the chronic injury and healing response. Intracoronary irradiation therapy (brachytherapy) was the most effective therapy for treating in-stent restenosis until the recent favourable outcomes with drug-eluting stents. Brachytherapy was also investigated as adjunctive therapy directly after stenting or balloon angioplasty to prevent the occurrence of restenosis. However, long-term results are disappointing and a high percentage of late thrombotic occlusion has been reported. In chapter 4 a case-report is presented with late occlusion five years after balloon angioplasty and adjunctive brachytherapy, while 3 year follow-up angiography had shown a patent vessel! Impaired healing response of the vessel wall after radiation therapy is thought to be the cause of these late (thrombotic) occlusions. Chapter 5 shows the sequelae of the early drug-eluting stent period, when the largest available stent size was 3.0 mm. To achieve acceptable stent apposition in large coronary vessels, stents were up-sized with larger balloons. This can lead to stent strut fracture and as shown in this case the combination of less local drug elution and the direct trauma of the broken stent struts as well as damage to the polymer can lead to restenosis, even in large vessels and with the use of drug-eluting stents. The second part of this thesis is focussing on endothelial dysfunction after percutaneous coronary interventions (PCI). In chapter 6 vascular permeability as a parameter of regeneration of a mature endothelial lining after balloon angioplasty or stenting was investigated, both early and late after the intervention. Dye-exclusion tests showed persistent vascular permeability up to 3 months after the intervention, being the most pronounced in the stented vessels. This indicates immature endothelial functional recovery and this was correlated with distinct morphologic characteristics, such as endothelial retraction, the expression of surface folds and the adhesion of leukocytes. Brachytherapy is associated with a delayed vascular healing response. In chapter 7 we investigated whether more endothelial dysfunction could be demonstrated in patients treated 6 months before with stenting and adjunctive brachytherapy or no brachytherapy. In both groups, endothelial function was still abnormal after 6 months, like shown before by Caramori et al. in bare stents, but no difference could be demonstrated. Investigating endothelial function 6 months after drug-eluting stent implantation in chapter 8 led to the remarkable observation that endothelial function was severely disturbed, while in the control group no significant paradoxal vasoconstriction ( as a sign of endothelial dysfunction) could be demonstrated. This is not in accordance with the excellent clinical results up to three year after drug-eluting stent implantation. This outcome should be investigated in a larger patient population, but is reason for some concern and may be related to the slight increase in stent thrombosis seen after drug-eluting stent implantation, particularly late stent occlusions. If confirmed, adjunctive medical therapy like ACE-inhibitors as well as already advised cholesterol-lowering therapy for all patients after drug­eluting stents should be considered, next to the already implemented prolonged use of double anti-platelet therapy. The subset of patients from the study reported in chapter 8 was used to study the relation between local endothelial function and shear stress in chapter 9. Low shear stress has been correlated to endothelial dysfunction but this has only been shown in vitro. Using sophisticated mathematical calculations, 3D reconstructions of the coronary segments distal to the implanted stents were made. Incorporating coronary flow velocity data and studying the patients after intracoronary acetylcholine infusions, correlations between local shear stress and local endothelial dysfunction (vasoconstriction) could be found. In regions with a shear stress of less than 1.3 Pa, a significantly larger vasoconstrictive response to acetylcholine could be seen compared to areas with shear stress of 1.3 Pa or more (normal to high shear stress). It is for the first time that such a correlation could be demonstrated in vivo. The third part of this thesis is focussing on coated and drug-eluting stents. Chapter 10 reports the findings of the use of a heparin-coated stent in porcine coronary arteries. This preclinical study led to the clinical BENESTENT 2 pilot and trial, showing a very low risk of stent thrombosis, despite a progressively milder anti-coagulant regime, ending with dual-platelet therapy, without post-procedural heparin. Today this is still the clinical practice. Over the last 10 years further attempts have been undertaken with different heparin stent- coatings to minimize the risk of stent thrombosis and reduce the incidence of in-stent restenosis. Chapter 11 provides an update on those attempts, highlighting three different heparin-coatings, the HepacoatTM, the HepamedTM and the CorlineTM coating. Clinical trials have shown very low rates of subacute stent thrombosis of 0.2 %. The average incidence of subacute stent thrombosis in bare metal stent is around 1 %. However, the other goal to reduce the rate of in-stent restenosis has not been reached and no significant difference has emerged from the different trials. There is a nice for heparin-coated stents in highly thrombotic subsets of patients or patients with a contraindication for prolonged antiplatelet therapy, but availability of the stents has become a problem. After attempts with passive stent coatings newer concepts with drug-elution from a stent­based polymer, or even without polymer were investigated. This is a fast evolving field of research which has led sofar to two commercially available drug-eluting stents with excellent clinical results in multiple large trials, the sirolimus-eluting stent (SES) (Cypher, Cordis Co, Warren, NJ, USA) and the paclitaxel-eluting stent (PES) (Taxus, Boston Scientific, Galway, Ireland). Next to these stents, multiple drug-eluting stents are in the pre-clinical or clinical testing phase. Chapter 12 is providing an update up to February 2004 of this field. In chapter 13 the first registry results are reported of the use of SES in the highly thrombotic environment of patients with an acute myocardial infarction. Concerns of higher risk of stent thrombosis in drug-eluting stents have been expressed multiple times and though it never has been substantiated, this fear has led to restrictive use in acute myocardial infarction. In this series of 186 consecutive patients no stent thrombosis was diagnosed and only 1.1 % of patients needed target vessel reintervention at 300 days follow-up compared to 8.2 % in the bare stent group in this study. Chapter 14 investigated the safety of the PES for the same indication of primary PCI for acute myocardial infarction. PES is also effective, but the slightly higher risk of subacute thrombosis of 2.9 % raises some concern. Half of these stent thromboses were seen in stented bifurcation lesions. This suggests that bifurcation stenting should be avoided in the setting of an acute myocardial infarction if possible and bifurcation treatment should be kept as simple as possible. Late stent thrombosis after 30 days was not seen, which is very reassuring. In Conclusion this thesis demonstrated that vessel wall injury occurs during coronary intervention, that this vessel wall injury can even increase after the acute injury in the case of stenting and that this injury leads to neointimal proliferation. Endothelial dysfunction is still present months after the intervention, but no worse endothelial function could be demonstrated late after brachytherapy compared to no brachytherapy. In contrast, after SES implantation severe endothelial dysfunction was still detectable after 6 months. A correlation could be found between local endothelial dysfunction and areas of low shear stress. Despite this, SES and PES show excellent intermediate-term clinical results and no late stent thrombosis could be found in patients treated during acute myocardial infarction. However, delayed vascular healing with prolonged endothelial dysfunction is reason for some concern and despite extended duration of double anti-platelet therapy, stent thrombosis rates are similar to those in bare stents and the timing is less predictable. More attention towards improving endothelial function after intervention of the culprit lesion seems advisable. May be this can be achieved by adjunctive medication like ACE-inhibitors and aggressive cholesterol lowering.