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The authors regret for H.M. Warda the affiliation ‘Tanta University Hospital, Tanta, Egypt' was not included in the original article and it has now been included. The authors would like to apologise for any inconvenience caused. © 2019 Elsevier B.V.

Acute coronary syndromes contribute a substantial part of the global disease burden. To realise a reduction in mortality and morbidity, the management of patients with these conditions involves the integration of several different approaches. Timely delivery of appropriate care is a key factor, as the beneficial effect of reperfusion is greatest when performed as soon as possible. Innovations in antithrombotic therapy have also contributed significantly to improvements in the prevention of ischaemic complications. However, with the use of such treatment an increase in the risk of bleeding is inevitable. Therefore, the greatest challenge is now to obtain an optimal balance between the prevention of ischaemic complications and the risk of bleeding. In this regard, identification of patients at highest risk of either one is essential. © 2012 The Association for the Publication of the Journal of Internal Medicine.

The aim of this thesis was to evaluate new developments in the treatment of patients with ischemic heart disease, with special focus to the invasive evaluation of plaque characteristics in patients with ST-segment elevation myocardial infarction (STEMI) and treatment of STEMI patients with drug-eluting stents. Additionally, the results of two preclinical studies were described investigating a new mouse model of focal drug-delivery to inhibit restenosis and an evidence based treatment protocol was described for patients with a acute myocardial infarction. Summary The introduction and outline of this thesis (Chapter 1) describes current insights in the pathophysiological development of ischemic heart disease and the corresponding clinical syndromes. Basically, ischemic heart disease is caused by atherosclerosis, which is a chronic inflammatory process of the coronary arteries leading to narrowing of these arteries and limitation of coronary blood flow and/or plaque rupture or erosion leading to intracoronary thrombosis. Clinically, this results in stable angina or an acute coronary syndrome with or without ST-segment elevation on the ECG. Particularly acute coronary syndromes lead to morbidity and mortality due to acute and chronic complications as heart failure and ventricular arrhythmias. Based on these pathophysiological insights and the clinical complications several medical, supportive and invasive strategies have been developed to treat the patients with ischemic heart disease, such as: the Coronary Care Unit, _-blockers, aspirin, HMG-coA-reductase inhibitors (statins), ACE-inhibitors and AT-II blockers, aldosteron blockers, thrombolysis, acute or elective mechanical revascularization by Percutaneous Coronary Intervention (PCI; with or without stent implantation) or Coronary Artery Bypass Grafting (CABG) and Implantable Cardioverter Defibrillators (ICD__s). To optimize the use of all these treatment modalities guideline based implantation protocols have been developed, which further seem to improve patient__s prognosis. In Chapter 1 specific attention is paid to the development of in-stent restenosis. Restenosis is the re-narrowing of a treated vessel segment after PCI. After balloon angioplasty, restenosis is caused by acute recoil, neointimal growth and chronic constrictive remodeling. Stent implantation prohibits elastic recoil and chronic constrictive remodeling but enhances neointimal growth. Although stent implantation decreases the rate of restenosis, 7-15% of the patients need additional revascularization due to in-stent restenosis. One of the latest developments in the treatment of ischemic heart disease is the introduction of drug-eluting stents. A drug-eluting stent combines its__ mechanical properties to scaffold the vessel and its__ focal application, which allows local delivery of anti-restenotic drugs using the stent as a drug-delivery platform. By using drugeluting stents, acute recoil and chronic constrictive remodeling is prohibited by the stent and neointimal growth is inhibited by the anti-proliferate drug released from the stent. Several drug-eluting stents were compared with bare-metal stents in randomized controlled trials. Some of the investigated drug-eluting stents were associated with a worse clinical outcome, because of an increased rate of in restenosis or stent thrombosis. However, treatment with some drug-eluting stents did significantly reduce the need for repeat revascularization without serious adverse effects (polymer based sirolimus-eluting stent (CypherTM), polymer based paclitaxel-eluting stent (TaxusTM), zotarolimus-eluting stent (EndeavorTM) and everolimus-eluting stent (Xience VTM/PromusTM). Although these stent differ in their biological potency to inhibit neointimal growth, clinical outcome seems comparable, at least in stable non-complex lesions. There is still lot of debate about the long-term safety of drug-eluting stents, especially in real world patients and lesions, since histopathological data demonstrate delayed endothelial healing. Especially after withdrawal of dual anti-platelet therapy, this delayed endothelial healing may be clinically important, since this is a strong predictor of stent thrombosis. Moreover, due to less neointimal growth and effects of the released drug on the vessel wall, late stent malapposition occurs more frequently after drug-eluting stent implantation, which may also increase the risk of late stent thrombosis. Chapter 2 describes the result of a study investigating a mouse model to test various antirestenotic drugs. In this model restenosis is induced by placing a poly(_-caprolactone) cuff around one off the femoral arteries of a mouse, using the contra-lateral femoral artery as a control. Within the cuff, various anti-restenotic compounds can be dissolved, which are released over time out of the polymer. Using this model, reproducible restenosis-like lesions, containing predominantly smooth muscle-actin positive cells, can be induced. Loading the cuff with the anti-restenotic drugs paclitaxel and rapamycin resulted, in vitro, in a sustained and a dose-dependent release for at least 3 weeks. Paclitaxel- and rapamycin-eluting poly(_-caprolactone) cuffs placed around the femoral artery of mice, in vivo, significantly reduced intimal thickening by 76_2% and 75_6%, respectively, at 21 days. Perivascular sustained release of both anti-restenotic drugs is restricted to the cuffed vessel segment with no systemic adverse effects or effect on cuffed contra-lateral femoral artery. Therefore, this drug-eluting poly(_-caprolactone) cuff mouse model is an easy and rapid tool to evaluate anti-restenotic drugs to be incorporated in a drug-eluting stent. The aim of Chapter 3 was to evaluate the local and systemic effects of dexamethasone on restenosis and vascular integrity. Dexamethasone is a potent anti-inflammatory and anti-proliferate drug which may be suitable as anti-restenotic drug as part of a drug-eluting stent. The mouse model as described in Chapter 2 was used and the results were compared with systemic application of dexamethasone. Systemic dexamethasone treatment shows adverse effects in animals, such as delayed wound healing and weight loss. In contrast, local delivery of dexamethasone inhibits neointimal proliferation and has no systemic adverse effects. However, pathobiological examination of the cuffed femoral arteries, reveals a dose-dependent medial atrophy, a reduction in vascular smooth muscle cells and collagen content, an increase in apoptotic cell count and disruption of the internal elastic lamina. Thus, although dexamethasone reduces neointimal growth, it has serious adverse effects on vascular integrity. In Chapter 4 the efficacy of dexamethasone-eluting stents (DexametTM) to inhibit restenosis in patients with diabetes mellitus was evaluated. Diabetes mellitus is a strong predictor for in-stent restenosis. Dexamethasone is an anti-restenotic drug which cannot be applied systemically due to its__ side-effects, such as increased insulin resistance. 21 Patients with diabetes mellitus (38% insulin dependent) with 32 lesions were treated with dexamethasone-eluting stents. Excluded were patients with triple vessel disease, bifurcation lesions, previous revascularization of the culprit vessel, reference diameter smaller than 2.50mm or larger than 3.75mm. Event free survival at 12 months was 62%. Any revascularization procedure was performed in 33% and target lesion revascularization in 24% of the patients. At 6 months in-stent late loss was 1.07_0.64mm. Binary restenosis occurred in 28.1% of the lesions. The event free survival in insulin dependent diabetes mellitus was worse compared to non-insulin dependent diabetes mellitus (92.1 vs. 37.8%). Insulin dependent diabetic patients had higher in-stent late loss compared to non-insulin dependent diabetic patients (1.44_0.83 vs. 0.83_0.51mm). It was concluded that treatment with dexamethasone-eluting stents in patients with diabetes mellitus is no reasonable alternative to bare-metal stents, especially in patients with insulin-dependent diabetes mellitus. Chapter 5 describes the results of a study investigating the distribution, arc and location of calcified spots in culprit lesions of patients with ST-segment elevation myocardial infarction (STEMI). From Electron Beam Computed Tomography studies it is known that the extent of intracoronary calcium is related to the risk of coronary events. This study was performed in 60 patients using Intravascular ultrasound (IVUS) imaging. Calcifications in the culprit lesion and adjacent segments were classified and counted according to their arc (180_), length (6.0mm) and dispersion (number of spots per millimeter). Calcifications at the edge of a visible rupture or ulceration were considered to be related to the myocardial infarction. Compared to adjacent proximal and distal segments, the culprit lesion contained more calcified spots per millimeter (respectively 0.14, 0.10, and 0.21), which were mainly small calcified spots (arc 40% plaque burden; 2. necrotic core __0.5mm in length occupying >10% of the plaque area; 3. no fibrous tissue above the necrotic core and; 4. remodeling index >1.05. Lesion length was 13.7_6.9mm, maximum plaque burden was 68.8_7.6% and the remodeling index was 1.28_0.28. Positive remodeling was present in 81%; 98% of the lesions showed >40% plaque burden and 95% of the lesions showed a necrotic core, with a necrotic core length of 5.2_4.9mm and maximum percentage necrotic core area of 25.9_11.3%. A necrotic core without overlying fibrous tissue was present in 94%. Of the lesions, 68% fulfilled all IDTCFA criteria, which corresponds to histopathological findings. Chapter 7 describes the development of a guideline based treatment protocol (MISSION!) for patients with acute myocardial infarction (AMI) for all phases of AMI care (pre-hospital, in-hospital and outpatient). Although many evidence based guidelines describe treatment targets for AMI patients, it is well recognized that many AMI patients are not treated accordingly. Moreover, most implementation programs focus on acute and secondary prevention strategies during the index hospitalization phase only. The MISSION! protocol is based on the most recent American College of Cardiology/American Heart Association and European Society of Cardiology guidelines for patients with AMI. It contains a pre-hospital, in-hospital, and outpatient clinical framework for decision making and treatment up to 12 months after the index event. MISSION! concentrates on rapid AMI diagnosis and early reperfusion, followed by active lifestyle improvement and structured medical therapy. Because MISSION! covers both acute and chronic AMI phases, the design implies an intensive multidisciplinary collaboration among all regional health care providers. In Chapter 8 the results of the MISSION! Intervention Study are described (Current Controlled Trials number, ISRCTN62825862). This study is a single-blind, single center, randomized study comparing bare-metal stents (BMS) with sirolimus-eluting stents (SES) in 310 STEMI patients. The primary endpoint was in-segment late luminal loss (LLL) at 9 months. Secondary endpoints included late stent malapposition (LSM) at 9 months as determined by intravascular ultrasound imaging and clinical events at 12 months. Insegment LLL was significantly lower after SES implantation (0.12_43mm versus 0.68_0.57mm), with a mean difference of 0.56mm, 95%CI 0.43-0.68mm. Moreover, the event free survival at 12 months was higher in the SES group (86.0% versus 73.6%) and the target vessel failure free survival was also higher in the SES group (93.0% versus 84.7%). However, LSM at 9 months was significantly more often present after SES implantation (37.5% versus 12.5% in the BMS group). Rates of death, myocardial infarction and stent thrombosis were not different. Thus, SES implantation in STEMI patients is associated with a favorable mid-term clinical and angiographic outcome compared to treatment with BMS. However LSM raises concern about the long-term safety of SES in STEMI patients. Chapter 9 describes the results of the MISSION! Intervention Study for women and men. It has been recognized that women have higher in-hospital mortality when hospitalized for an AMI. Moreover, several studies demonstrated that women are at lower risk to develop restenosis. The advantage of drug-eluting stents in women needs therefore to be assessed. The in-segment LLL after BMS or SES implantation was significantly lower for women: 0.42_0.54mm versus 0.74_0.56mm (BMS) and -0.03_0.39mm versus 0.18_0.44mm (SES). The rate of negative in-segment LLL (LLL

Diabetes mellitus (DM) is a strong predictor of in-stent restenosis. This may be due to a higher level of vascular inflammation. We hypothesized that diabetic patients will benefit from dexamethasone-eluting stents, since local inflammation and consequently neointimal growth are suppressed and no systemic side effects will occur. Methods: 21 consecutive patients with DM with 32 lesions were treated with dexamethasone-eluting stents. Excluded were patients with triple vessel disease, bifurcation lesions, previous revascularization of the culprit vessel, and reference diameter smaller than 2.5 or larger than 3.75 mm. MACE (death, myocardial infarction, and revascularization) was counted at 12 months. At 6 months, angiographic follow-up was performed. Results: Of the patients, 38% had insulin-dependent DM. Lesion type was type A/B1 in 56% and B2/C in 44%. Lesion length was 15.7 ± 8.4 mm and the reference diameter was 2.83 ± 0.53 mm. Event-free survival at 12 months was 62%. Any revascularization procedure was performed in 33% and target lesion revascularization in 24% of the patients. At 6 months in-stent late loss was 1.07 ± 0.64 mm. Binary restenosis occurred in 28.1% of the lesions. The event-free survival in insulin-dependent DM was worse compared to non-insulin-dependent DM (92.1 vs. 37.8%; p < 0.01). Patients with insulin-dependent DM had higher in-stent late loss compared to non-insulin-dependent DM patients (1.44 ± 0.83 vs. 0.83 ± 0.51 mm; p < 0.01). Conclusion: Treatment with dexamethasone-eluting stents in patients with DM is associated with a relatively high restenosis rate. Our data suggest a differential effect of dexamethasone-eluting stents in insulin-dependent compared to non-insulin-dependent DM. © 2007 Elsevier Ireland Ltd. All rights reserved.

The introduction of drug-eluting stents (DES) to prevent in-stent restenosis is one of the major advances in interventional cardiology. Currently many types of DES are under evaluation for effectiveness and safety, a time-consuming and difficult procedure in humans. An animal model that allows rapid evaluation of the present and upcoming therapeutic approaches to prevent in-stent restenosis is most valuable and still lacking. Here, a perivascular cuff to induce restenosis was constructed of a poly(ε-caprolactone) (PCL) formulation suitable for the controlled delivery of drugs. Placing the PCL cuff around the femoral artery, in vivo, resulted in reproducible restenosis-like lesions containing predominantly smooth muscle-actin positive cells. Loading the cuff with the anti-restenotic compounds paclitaxel and rapamycin resulted, in vitro, in a sustained and dose-dependent release for at least 3 weeks. Paclitaxel- and rapamycin-eluting PCL cuffs placed around the femoral artery of mice in vivo significantly reduced intimal thickening by 76±2% and 75±6%, respectively, at 21 days. Perivascular sustained release of both anti-restenotic agents is restricted to the cuffed vessel segment with no systemic adverse effects or effect on cuffed contralateral femoral arteries. Drug-eluting PCL cuffs provide an easy and rapid tool to evaluate anti-restenotic agents to be used in combination with the DES strategies. © 2005 Elsevier Ltd. All rights reserved. Chemicals / CAS: macrogol 300, 37361-15-2; paclitaxel, 33069-62-4; polycaprolactone, 24980-41-4, 25248-42-4; rapamycin, 53123-88-9; aquaplast, caprolactone, 24980-41-4; Coated Materials, Biocompatible; Drug Carriers; Drug Implants; Immunosuppressive Agents; Paclitaxel, 33069-62-4; Polyesters; Sirolimus, 53123-88-9

Aim of this thesis was to evaluate contemporary care and prognosis for patients with acute coronary syndrome and identify pitfalls in its treatment. Complications after coronary stent implantation were explored and demonstrated that in sirolimus-eluting stents, the benefit of reduced repeat revascularization during one year after primary PCI was not sustained during long-term follow-up. Additionally, an increased risk of very late stent thrombosis was suggested. Late stent malapposition, more commonly observed after this stent type and suspected to be involved in the multifactorial etiology of stent thrombosis, is shown to persist in the greater portion of STEMI patients during long-term follow-up, depending on the degree of vessel wall remodelling and change in plaque burden. Women were identified as a sub-population with poorer prognosis early after STEMI. Identification of high-risk patients, and estimation of infarct size and prognosis, which a single measurement of troponin already may indicate, facilitates individualized treatment and likely results in better outcomes. Although numerous novel treatment modalities emerged in recent years, certain pitfalls become increasingly important. Major bleeding is one of them, responsible for an excess mortality amongst STEMI patients after primary PCI, and should be incorporated in risk stratification models for the choice of treatment strategy.