A Clinician's Contribution to Biomedical Engineering in Experimental Echocardiography

The research of this thesis has been focused on the biomedical engineering aspects of new techniques of echocardiography. In close collaboration with the engineers of the Experimental Echocardiography Department of the Thoraxcentre, Erasmus University, Rotterdam, new methods to measure coronary blood flow and arterial wall elasticity with intravascular ultrasound (IVUS) have been developed. We have also investigated the clinical application of these measurements and have tried to improve traditional techniques based on intracoronary Doppler wires. In another field, we have developed a method to determine the radiation dose delivered in the wall of coronary arteries treated with brachytherapy. in collaboration with the Emory University, Atlanta, GA. This method utilizes 3-dimensional IVUS reconstruction combined with radiotherapy treatment planning. Finally, the tools developed for the recording of the signals of intracoronary Doppler wires have been adapted, during a stay at the Cleveland Clinic Foundation, OK for the study of left ventricular mechanics and the compliance of the large arteries. This has been achieved by simultaneous acquisition of non-invasive pressure (with tonometry) and flow (with transthoracic Doppler echocardiography) signals. The fruits of an old and close collaboration with the Institute Biomedical Technology of the Ghent University can also be found in different chapters. This work is subdivided in five major parts, and a detailed introductory chapter precedes each one

Intravascular Ultrasound

Intravascular ultrasound (IVUS) is a cardiovascular imaging technology using a specially designed catheter with a miniaturized ultrasound probe for the assessment of vascular anatomy with detailed visualization of arterial layers. Over the past two decades, this technology has developed into an indispensable tool for research and clinical practice in cardiovascular medicine, offering the opportunity to gather diagnostic information about the process of atherosclerosis in vivo, and to directly observe the effects of various interventions on the plaque and arterial wall. This book aims to give a comprehensive overview of this rapidly evolving technique from basic principles and instrumentation to research and clinical applications with future perspectives

Four-dimensional imaging of thoracic target volumes in conformal radiotherapy

The goal of conformal radiotherapy (CRT) is to deliver the prescribed dose to a volume that closely conforms to the three-dimensional (3D) target volume while the dose to adjacent healthy tissues or organs at risk is minimized. Because the position of the target volume can change substantially both within and between radiation treatment fractions the fourth dimension, namely time, needs to be addressed as well. The consideration of time in the 3D treatment process is referred to as fourdimensional (4D) radiotherapy. Variations in the target volume position with time are mainly due to organ motion and patient and beam set-up deviations. Changes in the target volume position that occur within a treatment fraction are referred to as intra-fraction variation. Respiratory and cardiac motion are the main contributors to intra-fraction positional variations of thoracic and abdominal target volumes. In routine clinical practice thoracic and abdominal tumors are irradiated while the patient breathes freely. To account for target volume variations in size, shape and position and patient and beam set-up deviations, an empirical 3D margin is added to the clinical target volume to obtain the planning target volume (1, 2). The 3D margin is often derived from respiratory motion measurements in patients representative of the general population. Such a margin is not tailored to the individual patient and will therefore be suboptimal in most cases. Alternatively, the tumor motion in a specific patient can be determined as part of the treatment planning procedure. Fluoroscopy is most widely used for this purpose. However, tumors are often poorly visualized using this imaging modality. In addition, fluoroscopic data cannot directly be related to the treatment planning computed tomography (CT) data

Lumen-intima and media-adventitia segmentation in IVUS images using supervised classifications of arterial layers and morphological structures

Background: Intravascular ultrasound (IVUS) provides axial grey-scale images of blood vessels. The large number of images require automatic analysis, specifically to identify the lumen and outer vessel wall. However, the high amount of noise, the presence of artifacts and anatomical structures, such as bifurcations, calcifications and fibrotic plaques, usually hinder the proper automatic segmentation of the vessel wall. Methods: Lumen, media, adventitia and surrounding tissues are automatically detected using Support Vector Machines (SVMs). The classification performance of the SVMs vary according to the kind of structure present within each region of the image. Random Forest (RF) is used to detect different morphological structures and to modify the initial layer classification depending on the detected structure. The resulting classification maps are fed into a segmentation method based on deformable contours to detect lumen-intima (LI) and media-adventitia (MA) interfaces. Results: The modifications in the layer classifications according to the presence of structures proved to be effective improving LI and MA segmentations. The proposed method reaches a Jaccard Measure (JM) of 0.88 ± 0.08 for LI segmentation, compared with 0.88 ± 0.05 of a semiautomatic method. When looking at MA, our method reaches a JM of 0.84 ± 0.09, and outperforms previous automatic methods in terms of HD, with 0.51mm ± 0.30. Conclusions: A simple modification to the arterial layer classification produces results that match and improve state-of-the-art fully-automatic segmentation methods for LI and MA in 20MHz IVUS images. For LI segmentation, the proposed automatic method performs accurately as semi-automatic methods. For MA segmentation, our method matched the quality of state-of-the-art automatic methods described in the literature. Furthermore, our implementation is modular and open-source, allowing for future extensions and improvements.Fil: Lo Vercio, Lucas. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Grupo de Plasmas Densos Magnetizados. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Grupo de Plasmas Densos Magnetizados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: del Fresno, Mirta Mariana. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Grupo de Plasmas Densos Magnetizados. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Grupo de Plasmas Densos Magnetizados; ArgentinaFil: Larrabide, Ignacio. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Grupo de Plasmas Densos Magnetizados. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Grupo de Plasmas Densos Magnetizados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentin

Limitations and Long Term Outcome of Intracoronary Radiation Therapy With Catheter Based Systems and Radioactive Stents

__Abstract__ Balloon angioplasty was the first non-surgical therapeutic modality for coronary artery disease introduced in 1977. It was related with high rates of acute complications and restenosis that limited its application to a minority of patients with coronary artery disease with relatively simple lesion morphology. Continuous developments during the next decade led to the introduction of stents in 1986. They were proven extremely efficient in reducing acute complications, dramatically expanding the indications for percutaneous interventions. In addition they were associated with favourable outcome in reducing restenosis compared to balloon angioplasty but they were also limited by the development of in-stent restenosis. Instent restenosis remained a therapeutic challenge for almost a decade and many mechanistic and pharmacological attempts failed to solve it. Ionic forms of radiation (radioactive stents and localised catheter based intracoronary radiation therapy) were introduced. Radioactive stents showed no benefit compared to conventional stenting. However intracoronary brachytherapy, which was first applied in human coronaries in 1995, was proven effective for the treatment of in-stent restenosis (secondary prevention of restenosis). Its efficiency for treatment of de novo lesions (primary prevention of restenosis) especially in combination with the use of stents is limited. In 2001 drug eluting stents were introduced into clinical practice and they revolutionised the treatment of coronary artery disease. They are the first therapeutic modality in interventional cardiology expected to show equal or superior results in comparison to coronary artery by pass surgery. In Europe were conducted the majority of the human trials with radioactive stents and pioneering and exploratory studies with intracoronary radiotherapy with catheter based systems mainly with beta emitters for de-novo lesions. This thesis addresses issues central to both of these therapeutic modalities

A Review on Advances in Intra-operative Imaging for Surgery and Therapy: Imagining the Operating Room of the Future

none4openZaffino, Paolo; Moccia, Sara; De Momi, Elena; Spadea, Maria FrancescaZaffino, Paolo; Moccia, Sara; De Momi, Elena; Spadea, Maria Francesc

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

Het doel van dit proefschrift was het bestuderen van de vaatwandreactie na interventies in de kransslagader. Hierbij werd gekeken naar acute en chronische vaatwandbeschadiging, endotheeldysfunctie en naar het gedrag van de nieuwste generatie stents, de zogenaamde “drug-eluting stents” (DES), waarbij na implantatie gedurende een bepaalde tijd langzaam een medicijn diffundeert uit de stentcoating ter voorkoming van in-stent restenose. Deze medicijnen worden namelijk gerelateerd aan vertraagde genezing van de beschadigde vaatwand, wegens de sterke anti-proliferatieve werking van deze medicijnen. Het eerste deel van het proefschrift concentreert zich op de vaatwandbeschadiging die ontstaat door de interventie. Hoofdstuk 2 Beschrijft de vier fasen van de wondgenezing na het plaatsen van een stent, nl. de vroege trombotische respons, gevolgd door de recruteerfase gekenmerkt door het aantrekken van cellen, vervolgens de proliferatieve fase en tot slot de helingsfase. In hoofdstuk 3 wordt aangetoond dat de initiele vaatwandschade de eerste weken na de interventie zelfs nog toeneemt. In een varkensmodel worden twee verschillende stenttypes onderzocht in de kransslagader. Persisterende ontstekingsreactie en het verschil in stentontwerp lijken van invloed op de vaatwandschade en de helingsrespons. Voor de goede resultaten van de nieuwe DES was intracoronaire bestralingstherapie (brachytherapy) de meest effectieve therapie voor de behandeling van restenose in de stent. Daarnaast werd ook onderzocht of brachytherapy deze in-stent restenose zou kunnen voorkomen. De langetermijn resultaten bleken teleurstellend en vooral late stenttromboses werd frequent gezien, resulterend in een afsluiting van het vat. Hoofdstuk 4 beschrijft een patient waarbij 5 jaar na de behandeling en preventieve brachytherapie het bloedvat alsnog afgesloten raakt, terwijl het bij de 3-jaarscontrole nog fraai open was. De sterk vertraagde wondgenezing door de bestraling speelt waarschijnlijk een rol in deze erg late complicaties. In de begintijd van de DES waren er alleen maar relatief kleine maten beschikbaar. Om toch iedereen te kunnen laten profiteren van deze goede stents werden ze ook gebruikt in grotere vaten. Vervolgens werd de stent met een grotere balloon nagerekt. Hoofdstuk 5 laat zien dat dit kan leiden tot een breuk in de stent en re-stenose. Door de scherpe gebroken stentstruts, beschadigde polymeercoating en ter plekke minder effectieve dosering van het medicament dat re-stenose tegen moet gaan, kan deze stentbreuk alsnog leiden tot re-stenose, zelfs in grote vaten waar dit normaliter zelden voorkomt. Het tweede deel van dit proefschrift bestudeert de endotheelfunctie na interventies in de kransslagader. In hoofdstuk 6 werd vaatwandpermeabiliteit as marker van herstel van een volgroeide endotheellaag bestudeerd, zowel na ballonangioplastiek als na stenting, zowel vroeg als laat na de behandeling. Abnormale permeabiliteit kon worden aangetoond tot 3 maanden na de behandeling, waarbij dit meer uitgesproken was na stenting dan na ballonangioplastiek. Dit impliceert incompleet herstel van de endotheellaag. Hierbij konden karakteristieke morfologische veranderingen van de endotheelcellen worden aangetoond. Zoals boven reeds genoemd is de wondgenezing vertraagd na brachytherapie. In hoofdstuk 7 werd onderzocht of ernstiger endotheeldysfunctie aangetoond kon worden 6 maanden na stenting en brachytherapie dan na stenting zonder brachytherapie. In beide groepen was na 6 maanden de endotheelfunctie nog abnormaal, zoals ook reeds eerder aangetoond door Caramori et al. na stenting, maar een verschil tussen stent of stent en brachytherapie kon niet aangetoond worden. In hoofdstuk 8 werd de endotheelfunctie onderzocht 6 maanden na implantatie van de nieuwe generatie stents, de DES, en in dit geval de sirolimus-gecoate stent (SES). Dit leidde tot de opmerkelijke bevinding dat 6 maanden na de behandeling de endotheelfunctie ernstig gestoord was na implantatie van de SES, terwijl dit veel minder het geval was na een ongecoate stent. Dit is opvallend aangezien de klinische resultaten met inmiddels een follow-up van ruim 3 jaar uitstekende resultaten laten zien van deze stent. Deze bevinding zal moeten worden bevestigd in een veel grotere groep patienten, maar het roept wel op tot waakzaamheid en langdurige follow-up. Hoewel in grote studies nooit hard aangetoond, is er toch een vermoeden op een iets verhoogde kans op stenttrombose bij het gebruik van DES, vooral na het voortijdig stoppen van bloedplaatjesaggregatieremmers. Het langdurig gebruik van dubbele plaatjesaggregatieremmende medicatie is inmiddels reeds gebruikelijk, maar misschien zou een ACE-remmer na stenting ook standaard moeten worden net als cholesterolverlagende medicatie. Beide medicijnen hebben bewezen gunstig effect op atheroscleroseprogressie en een gunstig effect op het endotheel. In hoofdstuk 9 werd de relatie bestudeerd tussen locale endotheelfunctie en shear stress (schuifspanning). Tot nu toe is alleen in “in vitro” onderzoeken een relatie tussen low shear stress en endotheeldysfunctie aangetoond. Door gebruik te maken van wiskundige rekenmodellen konden 3D reconstructies worden gemaakt van de coronairvaten uit angiografische plaatjes en door middel van correlatie met gemeten bloedstroomsnelheden tijdens acetylcholineinfusie in de kransslagaderen, kon de relatie tussen shear stress en endotheeldysfunctie (vaatvernauwing op acetylcholine) worden bestudeerd. Gebiedjes met een lage shear stress van < 1,3 Pa gaven een significant grotere vaatvernauwing na acetylcholine vergeleken met gebiedjes met een hogere shear stress. Het is voor de eerste keer dat dit in vivo is aangetoond. Het derde deel van dit proefschrift concentreert zich op gecoate stents en DES. Hoofdstuk 10 beschrijft de resultaten van het gebruik van heparine-gecoate stents in kransslagaders van biggen. Deze preklinische studie leidde tot de bekende klinische studies, de BENESTENT 2 pilot en trial. Hierbij werd de veiligheid van de heparine­gecoate stent aangetoond zonder een verhoogd risiko op stenttrombose met alleen nabehandeling met twee verschillende plaatjesaggregatieremmende medicamenten. Dit is 8 jaar later nog steeds de gebruikelijke therapie. De afgelopen 10 jaren zijn nog diverse studies verricht met verschillende soorten heparine-gecoate stents om het risiko op stenttrombose te minimaliseren en het percentage in-stent restenose te verminderen. Dit eerste was succesvol met zelfs trombosepercentages ver onder de 0,5 % ten opzichte van ongeveer 1 % in metalen stents. Helaas is een significant reductie van in-stent restenose nooit aangetoond. Hoofdstuk 11 geeft een overzicht van deze studies. De boven reeds genoemde DES hebben inmiddels zeer goede resultaten laten zien in grote studies en worden in snel toenemende mate gebruikt in plaats van metalen stents. Tot nu toe zijn twee van dit soort stents in grote trials onderzocht en commercieel op grote schaal verkrijgbaar, nl. de sirolimus-eluting stent (SES) (Cypher, Cordis Co, Warren, NJ, USA) en de paclitaxel-eluting stent (PES) (Taxus, Boston Scientific, Galway, Ireland). Hoofdstuk 12 geeft een overzicht van de preklinische en klinische studies met diverse DES tot februari 2004. In Hoodstuk 13 worden de eerste 186 patienten beschreven die in het ErasmusMC werden behandeld met een SES voor een acuut hartinfarct. Hoewel een patient met een acuut hartinfarct een duidelijk verhoogde stollingsneiging van zijn bloed heeft in de acute fase, bleek het gebruik van de SES ook in deze setting veilig en zonder verhoogde risiko’s op stenttrombose. Ook bleek dat patienten die met een SES behandeld werden vrijwel nooit terug hoefden te komen voor een herinterventie in het behandelde vat gedurende een follow-up van 300 dagen (1,1% vs. 8,2 % voor patienten behandeld met een metalen stent). In hoofdstuk 14 werd de andere DES nl. de PES geevalueerd voor dezelfde indicatie. Ook deze stent liet goede resultaten zien, echter er werden enkele patienten teruggezien met stenttrombose (2,9 %). De helft van deze patienten waren in de acute fase behandeld voor een afsluiting op een vertakking in de kransslagader. Hierbij waren beide takken gestent, en hoewel deze getallen erg klein zijn, zou dit mogelijk een verhoogde stenttrombose kans geven. Late stenttromboses werden niet gezien en na 1 jaar was er geen significant verschil in effectiviteit tussen de SES en de PES. Conclusie: Dit proefschrift laat zien dat de vaatwand beschadigd raakt tijdens de behandeling van vernauwingen in de kransslagader met ballonangioplastiek of stentplaatsing. Deze beschadiging kan zelfs nog toenemen in de eerste weken na stentplaatsing. Dit wordt gevolgd door een genezingsreactie met vorming van een neointima. Bij excessieve schade is de kans groter op in-stent restenose door meer neointimaproliferatie. Endotheeldysfunctie is nog maanden na de interventie in het bloedvat aantoonbaar. Hoewel deze genezingsfase wordt vertraagd door bestralingstherapie kon na 6 maanden geen verschil in endotheeldysfunctie worden aangetoond in bestraalde patienten tov niet-bestraalde patienten. Daar stond tegenover dat in patienten die een SES ontvingen de endotheelfunctie na 6 maanden nog sterk gestoord was. Ook kon in deze patientengroep een relatie aangetoond worden tussen gebieden van lage schuifspanning (shear stress) en locale endotheeldysfunctie. Ondanks dit zijn de middellange termijn resultaten van SES en PES uitstekend en kon zelfs in de zeer trombogene setting van het acuut hartinfarct geen verhoogde neiging tot late stenttrombose aangetoond worden, als uiting van vertraagde vaatwandgenezing. Desalniettemin is vertraagde wondgenezing, gepaard gaand met langdurige endotheeldysfunctie reden tot enige zorg. Ondanks de forse verlenging van de behandelduur met twee bloedplaatjesaggregatieremmers is de incidentie van stenttrombose vergelijkbaar met ongecoate stents en het optreden ervan minder voorspelbaar. Het lijkt verstandig na het opheffen van de belangrijke vernauwing meer aandacht te besteden aan de kwaliteit van het endotheel. Dit zou misschien kunnen door een groter gebruik van ACE-remmers na de PCI alsmede door aggresieve cholesterolverlaging.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