Proefschriften 2009

Promotie ScholteCardiac imaging for risk stratification in asymptomatic diabetes

Arthur J.H.A. Scholte

Promotores: Prof. dr. J.J. Bax, Prof. dr. E.E. van der Wall
19 november 2009

In this thesis we evaluated the value of different cardiac imaging techniques for risk stratification in asymptomatic patients with diabetes mellitus (DM) type 2. Chapter 1 of this thesis provided an overview of the prevalence of DM, its complications and the background of the different non-invasive imaging modalities that are used for risk stratification. In chapter 2 we focused on the potential role of stress myocardial perfusion imaging (MPI) and computed tomography coronary artery calcium (CAC) scoring as two complementary approaches for screening asymptomatic patients with DM type 2. In chapter 3 we assessed prospectively evidence for silent coronary artery disease (CAD) in asymptomatic patients with DM type 2 by single photon emission computed tomography (SPECT) MPI, CAC scoring, and multislice computed tomography (MSCT) coronary angiography. In chapter 4 we evaluated the prevalence of CAD as well as plaque morphology in asymptomatic patients with DM type 2 using MSCT. In addition, the relation between CAC scores and MSCT findings was explored. In chapter 5 the prevalence of an abnormal stress MPI study in a cohort of truly asymptomatic patients with DM type 2 using SPECT MPI was evaluated. In chapter 6 we described a case report of a patient who despite early identification of CAD, followed by risk factor modification and aggressive medical therapy, suffered a silent myocardial infarction. The aim of the study in chapter 7 was to evaluate whether subclinical left ventricular systolic dysfunction was independently related to coronary atherosclerosis and if it could provide incremental information over baseline characteristics to identify patients having CAD. The purpose of the study in chapter 8 was to evaluate the prevalence of cardiac autonomic neuropathy (CAN) in patients with DM type 2 using heart rate variability and 123I‑metaiodobenzylguanidine myocardial scintigraphy. The prognostic value of all above mentioned cardiac imaging techniques for the risk stratification of asymptomatic patients with type 2 DM will be determined in follow-up of this cohort.

Promotie RezaMagnetic resonance imaging of atherosclerosis; studies in visceral obesity

RezaAlizadeh Dehnavi

Promotores: Prof. dr. J.A. Romijn, Prof. dr. A. de Roos, Prof. dr. J.W. Jukema
6 oktober 2009

The aim of this thesis was to explore the relation between visceral obesity and the accompanying metabolic disturbances, systemic inflammation and the atherosclerotic process. First a new technique of magnetic resonance imaging of the carotid artery at the magnetic field strength of 3 Tesla was developed and validated. This technique was shown to define vessel wall characteristics of the carotid artery with high reproducibility. In Part 2 of the thesis visceral obesity is phenotyped. In visceral obese subjects the presence of metabolic syndrome is associated with increased maximum vessel wall thickness of the carotid bulb approaching the level observed in patients who recently suffered from a ST-segment elevation myocardial infarction (STEMI). Plasma levels of C-reactive protein (CRP) correlated with vessel wall thickness in the carotid artery, and this correlation was independent of visceral obesity and independent of adipose tissue distribution in visceral and subcutaneous deposits. In addition, CRP was shown to affect atherosclerosis through interactions with lipoprotein metabolism, in particular apolipoprotein C1 (ApoC1).

Part 3 describes the results of a double-blinded, placebo controlled, randomized clinical trial that compares rosiglitazone in addition to intensive lifestyle treatment to lifestyle treatment alone on the progression of atherosclerosis and the cardiovascular risk profile of visceral obese male subjects with the metabolic syndrome and an elevated basal inflammatory status, but without established cardiovascular disease and type 2 diabetes mellitus. Follow-up was 52 weeks. Lifestyle treatment alone improved cardiovascular risk factors. The addition of rosiglitazone to lifestyle treatment reduced plasma CRP levels, increased the number of circulating hematopoietic stem cells, but did not prevent the progression of atherosclerosis. The observations of this study underline the impressive impact of lifestyle treatment on the cardiovascular risk profile of visceral obese subjects.

Promotie KraaijenveldIdentification of therapeutic targets in coronary artery disease: from patients to mice and back

Adriaan O. Kraaijeveld

Promotores: Prof. dr. E.A.L. Biessen, Prof. dr. J.W. Jukema, Prof. dr. T.J.C. van Berkel
1 oktober2009

 

Atherosclerosis is currently viewed as an inflammatory disease in which the initiation and progression of the atherosclerotic plaque towards a rupture-prone, unstable plaque is driven by leukocyte recruitment mediated by various inflammatory mediators. Part 1 of the thesis is devoted to the relation between cardiovascular disease and cytokines. Plasma samples of patients with unstable angina pectoris (UAP), assayed for chemokines and inflammatory mediators, demonstrated increased levels of CCL5 and CCL18 as compared to stabilized patients. From day 2 onwards, plasma levels of CCL5, CCL18 and sCD40L levels fell in all UAP patients. Elevated levels of CCL5 and CCL18 predicted future cardiovascular adverse events, whereas elevated levels of CRP and sCD40L did not. Human atherosclerotic plaques show abundant expression of CCL18. Administration of CCL18 for 2 weeks to atherosclerotic ApoE-/- mice on a fat-rich diet was observed to promote plaque progression although the plaque macrophage content decreased. CCL18 overexpression of the plaques by adenoviral gene transfer did not lead to differences in plaque size or composition except for an increase in CD3+ T-cells. Patients suffering from acute myocardial infarction (AMI) demonstrated elevated levels of CCL3, like patients with UAP. In the latter group baseline upper quartile levels of CCL3 were correlated with future acute coronary syndromes. In mice with AMI circulating levels of CCL3 were elevated, while CCR5+ T-cell numbers were increased as well, suggestive of CCL3 driven T-cell homing towards the ischemic area.

Part 2 of the thesis is devoted to the genes that are associated with atherosclerosis. Compared to young LDLr-deficient mice, old LDLr-deficient mice when put on a fat-rich diet for 8 weeks demonstrated smaller plaque size in the carotid artery and in the aortic root. Forty genes appeared differentially regulated upon aging, one of which was Quaking. With vascular aging this gene is upregulated and atherosclerotic plaques contain the Quaking protein. Determination of single nucleotide polymorphisms (SNPs) in the Quaking gene in patients of the prospective GENDER Study revealed 7 SNPs that were associated with risk for or protection against restenosis after percutaneous coronary intervention.

Promotie WinterFrom cardiogenesis to cardiac regeneration; focus on epicardiumderived cells

E.M. Winter

Promotores: Prof. dr. A.C. Gittenberger-de Groot, Prof. dr. R.E. Poelmann
15 oktober2009

cum laude

During cardiac development the proepicardial organ, a specific component of the second heart forming field, gives rise to the epicardial layer of the heart. Epicardium-derived cells (EPDCs) are generated from this epicardial sheet by epithelial-mesenchymal transformation, after which they invade the myocardial wall. The EPDCs contribute to the developing heart through delivering interstitial fibroblasts, adventitial fibroblasts and coronary smooth muscle cells, thereby regulating important processes like formation of the compact myocardium, Purkinje fibers, endocardial cushions and vessels. After transplantation of human adult EPDCs into the infarcts of immuno-incompetent mice, vascularization at 2 weeks had improved, left ventricular function had improved at 2 and 6 weeks, and survival at 6 weeks had improved compared to infarcted mice hearts injected by culture medium. Engrafted EPDCs demonstrated a myofibroblast phenotype.

Injection of a combination of human EPDCs and human cardiomyocyte progenitor cells (CMPCs) into mice infarcts further improved LV function at 6 weeks compared to single EPDC or CMPC transplantation, which themselves each enhanced cardiac performance compared to control vehicle injection. But none of the engrafted human cells differentiated into cardiomyocytes or endothelial cells. Finally, a method to track stem cells by MRI was investigated. To this purpose, EPDCs were loaded with iron oxide particles, subsequently incubated with oxygen (living cells) or nitrogen (dead cells), and injected in mice infarcts. Hypointense spots on MRI images corresponded with iron-loaded cells. However, in the dead-EPDC recipients, all iron-positive cells appeared to be macrophages, while the living-EPDC recipients also contained engrafted iron-loaded EPDCs. It is concluded that iron-labeling of cells is inadequate for fate determination of transplanted cells in the immuno-deficient host, since dead cells produce an MRI signal indistinguishable from incorporated living cells.

Promotie UmarMolecular and cellular characterization of cardiac overload-induced hypertrophy and failure

S. Umar

Promotor: Prof. dr. A. van der Laarse
19 juni2009

Cardiac overload leads to structural and functional changes of the myocardium, including hypertrophy and remodeling. On the cellular level cardiac overload is sensed by stretch receptors, such as integrins. These transmembrane proteins bind to the extracellular matrix on the outside and to the cytoskeleton on the inside of the cell. Activation of integrins of isolated rat cardiomyocytes by a soluble integrin ligand, a pentapeptide containing Arg-Gly-Asp (RGD), resulted in hypertrophy of the cells. The hypertrophic response was nitric oxide (NO)-dependent as a general NOS inhibitor, L-NAME, suppressed hypertrophy and exogenously applied NO-donor, nitroprusside, could rescue the L-NAME-induced suppression of hypertrophy. In patients with heart failure, before and 6 months after onset of cardiac resynchronization therapy (CRT), measurement of serum levels of markers of collagen synthesis and collagen degradation revealed that CRT-induced reverse remodeling of the left ventricle (LV) was associated with an increased collagen synthesis rate. In a rat model of pulmonary artery hypertension (PAH), monocrotaline (MCT) administration resulted in PAH and right ventricular (RV) failure, characterized by RV hypertrophy and depressed RV ejection fraction at 30 days. MCT-treated rats that received at 2 weeks intravenously mesenchymal stem cells from rats with MCT-induced PAH showed preserved pulmonary structure, less PAH, less RV hypertrophy and preserved RV function at 4 weeks, compared to MCT-treated rats that received only i.v. saline. Isolated LV and RV cardiomyocytes from rats without and with PAH were analyzed by electrophysiologic techniques. An interesting phenomenon observed in RV cardiomyocytes of healthy rats and rats with PAH was depolarization-induced automaticity. This arrhythmogenic mechanism may occur at the boundary of ischemic and nonischemic myocardium where ischemic cardiomyocytes could depolarize neighboring nonischemic cardiomyocytes.

Promotie PijnappelsElectrophysiological deterioration and resurrection in the scarred heart

Daniel A. Pijnappels

Promotores: Prof. dr. M.J. Schalij, Prof. dr. A. van der Laarse
18 juni2009

cum laude

 

The aim of this thesis was to explore, from a mechanistic and electrophysiological point of view, the integrative and functional aspects of cell modification and transplantation as therapeutic options to treat the damaged, ischemic heart.

It was shown that genetic modification of human ventricular scar fibroblasts, by forced expression of cardiac transcription factors, improved their electrical properties and reduced dyssynchrony between two adjacent fields of cardiomyocytes. However, such a modification of fibroblasts did not result in forced cardiomyogenic differentiation. Importantly, fibroblasts which were first reprogrammed into pluripotent cells (induced pluripotent stem (iPS) cells), through forced expressing of only 4 transcription factors, were able to differentiate into functional cardiomyocytes, offering tremendous new perspectives in terms of patient-specific screening and treatment.
This thesis also showed that spatial integration of transplanted mesenchymal stem cells is a novel determinant of functional integration and may thereby affect the therapeutic outcome of cardiac cell therapy. As a result, physicians and scientists should think how to rebuild the myocardium, while taking into account its anatomical and anisotropic properties.

Promotie GademanFitness in chronic heart failure: effects of exercise training and of biventricular pacing

M.G.J. Gademan

Promotores: Prof. dr. E.E. van der Wall, Prof. dr. M.J. Schalij
17 juni2009

 

The thesis describes the effects of exercise training and of cardiac resynchronization therapy (CRT) on fitness-related variables in the setting of chronic heart failure (CHF). Exercise training increased baroreflex sensitivity (BRS) and heart rate variability (HRV) and reduced sympathetic outflow, plasma levels of catecholamines, angiotensinII, vasopressin and brain natriuretic peptides at rest. As an effective exercise training protocol is often difficult to perform in patients with CHF, stable untrained CHF patients were either trained with bicycle exercise or with transcutaneous electrical nerve stimulation (TENS). By applying TENS in the form of periodic (2/s) burst stimulation to the feet, an exercise-associated somatosensory ergoreceptor stimulation pattern was mimicked. BRS increased significantly in the TENS group, but did not change in the exercise training group. The baseline values of the oxygen uptake-work relationship (D O2/DW) were normal in 58% of the CHF patients tested. In patients with decreased D O2/DW at baseline, exercise training improved D O2/DW. Metabolic and mechanical stress in the failing heart activates the cardiac sympathetic afferent reflex (CSAR) even at rest. Since CSAR afferent firing decreases arterial BRS, CRT-induced CSAR deactivation is likely accompanied by a BRS increase. Indeed, CRT acutely increased BRS and HRV. In responders of CRT at 6 months follow-up, but not in non-responders, CRT had increased BRS and HRV at baseline. Thus, a CRT-induced acute BRS increase at baseline has predictive value for the echocardiographic response to CRT. These findings suggest that the autonomic nervous system is actively involved in CRT-related reverse remodeling of failing hearts.

 

Promotie LiemImproving acute and long-term myocardial infarction care

Su-san S. Liem

Promotores: Prof. dr. E.E. van der Wall, Prof. dr. M.J. Schalij
23April2009

The main topic of the thesis was the design, implementation and subsequent evaluation of an all-phases integrated care program for patients with acute myocardial infarction (AMI): the MISSION! protocol. The aim of MISSION! was to improve daily care for patients with an AMI by implementation of the most recent guidelines into clinical practice, up to 1 year after the index event. Compared to a group of patients with AMI treated before the implementation of the MISSION! protocol, patients with AMI treated according to the MISSION! protocol had more primary percutaneous coronary intervention (PCI), the occluded coronary artery was opened more rapidly, more patients received β-blockers and ACE-inhibitors in the acute phase, at 1 year follow-up more patients used clopidogrel, β-blockers and ACE-inhibitors, and target cholesterol levels <4.5 mmol/L were achieved more often. To identify in an early stage patients prone to left ventricular (LV) remodeling, patients were examined with echocardiography within 48 hours after PCI for AMI. After 6 months follow-up echocardiography was repeated. Most patients with substantial LV dyssynchrony immediately after AMI develop LV dilatation during 6 months follow-up. A cutoff of 130 ms for LV dyssynchrony yielded a sensitivity of 82% and a specificity of 95% to predict LV remodeling at 6 months follow-up. In the MISSION! Intervention Study the safety and effectiveness of sirolimus-eluting stents (SES) were compared with those of bare metal stents (BMS). SES implantation in patients with AMI is associated with favorable mid-term clinical and angiographic outcome compared to treatment with BMS. However, late stent malapposition raises concern about the long-term safety of SES in patients with AMI. It is concluded that MISSION! has resulted in an increase of guideline adherence and improved clinical outcome.

 

Promotie de haanModulation of HDL metabolism. Studies in APOE*3-Leiden. CETP mice

W. de Haan

Promotores: Prof. dr. ir. L.M. Havekes, Prof. dr. J.W. Jukema
16 april2009

High plasma levels of low-density lipoprotein (LDL) and low plasma levels of high-density lipoprotein (HDL) are risk factors of atherosclerosis. Although current treatment includes LDL lowering, HDL-rising therapy is still not common. In this thesis the mechanisms underlying the HDL-raising effects of the classical lipid-lowering drugs fenofibrate, atorvastatin and niacin were analyzed. In addition, the effects of potential novel HDL-raising strategies, including torcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) activity, and apolipoprotein C1 (apoC1) on HDL metabolism were addressed. A mouse model was designed, the APOE*3-Leiden.CETP mouse, that showed a HDL rise upon administration of fenofibrate, atorvastatin and niacin, as occurs in humans. On a fat-rich cholesterol-containing diet these mice develop atherosclerosis. Fenofibrate and atorvastatin increased HDL by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool. Niacin decreased plasma cholesterol and triglycerides, and increased HDL-C. The latter was caused by niacin’s inhibition of CETP activity, as related to lower hepatic CETP expression, a reduced plasma (V)LDL pool, and increased apoAI by decreasing the clearance of apoAI from plasma. Torcetrapib, a drug designed to inhibit CETP activity, increased HDL-C in clinical trials, but did not potentiate the effects of atorvastatin on atherosclerosis, and led to adverse effects, including increased mortality in humans. In APOE*3-Leiden.CETP mice on fat-rich diet torcetrapib increased HDL-C and reduced atherosclerotic lesion size, but these lesions had a more inflammatory, less stable phenotype. Wild-type mice supplied with human apoC1 increased HDL-C levels, whereas apoC1-deficiency decreased HDL-C levels. Since apoC1 is the main endogenous HDL-associated CETP inhibitor, it can be a lead for the development of a new generation of CETP inhibitors aimed at increasing HDL levels and reducing risk of cardiovascular disease.

Promotie AlkemadeThe fetal origin of adult atherosclerosis; a study in ApoE and Ldlr mouse models

F.E. Alkemade

Promotores: Prof. dr. A.C. Gittenberger-de Groot, Prof. dr. L.M. Havekes
15 april 2009

This thesis describes the long-term consequences of an adverse intrauterine environment, created by maternal apoE-deficiency or Ldlr-deficiency, on the offspring’s susceptibility to atherosclerosis during adulthood. In mothers with apoE-deficiency, the fetal vascular development in apoE+/- offspring revealed profound vascular injury. In adulthood, collar-induced neointima formation in both chow and high-fat fed apoE+/- offspring from apoE-/- mothers was accelerated and aggrevated as compared to apoE+/- offspring from wild-type mothers. Thus, the susceptibility to neointima formation of adult arteries is programmed during prenatal development and manifests itself in the presence and absence of high-cholesterol diets in adult life. Thus, an adverse intrauterine environment provided by maternal apoE-deficiency poses a major risk for disease in adult life. In Ldlr-/- offspring of Ldlr-/- mothers, intrauterine exposure to maternal hypercholesterolemia resulted in fetal intimal thickening and profound spontaneous atherosclerosis in the adult stage. However, maternal hypercholesterolemia has limited effects on susceptibility to atherosclerosis in Ldlr+/- offspring indicating an important role for apoE in utero.

The programming of the fetus during development by maternal factors may be mediated by epigenetic mechanisms including DNA methylation or histone modifications. In endothelial cells and smooth muscle cells from apoE+/- offspring from apoE-/- mothers, the profiles of histone modifications and the responsible enzymes were clearly differentially affected compared to apoE+/- offspring from wild-type mothers. Thus, intrauterine programming of susceptibility for cardiovascular disease in adult life is, at least in part, established by adverse influences of maternal apoE-deficiency on chromatin modifications in the vasculature of the offspring.

 

Promotie KolditzCardiac development in relation to clinical supraventricular arrhythmias: focus on structure-function relations

D.P. Kolditz

Promotores: Prof. dr. M.J. Schalij, Prof. dr. A.C. Gittenberger-de Groot
8 april 2009

In part 1 of the thesis the (patho)physiological development of the isolating annulus fibrosus cordis and the etiological origin of clinical accessory pathway (AP)-mediated atrioventricular (AV) reentrant tachycardia (AVRT) in children and adults are analyzed in experimental animal (quail and mouse) models and human histological sections. In embryonic quail hearts persistent muscular AV connections were found that coursed through the fibrous annulus, associated with premature activation of the ventricular base. Longitudinal analysis of quail and mouse hearts revealed that these persistent APs decreased both in number and size at consecutive developmental stages and were mainly found in the posteroseptal region of the heart. Quail hearts in which the migration of epicardium-derived-cells (EPDCs) was mechanically inhibited showed marked defects in the annulus fibrosus with persistence of broad APs, functionally giving rise to ventricular preexcitation. Even in human embryonic heart up to 20 weeks of gestation APs near the lateral side of the tricuspid valve remained present. Isolation of the annulus fibrosus is normally completed postnatally, although occasionally persistent APs may act as substrates for transient AVRT in foetuses or neonates.

Part 2 describes historical and contemporary concepts of the ontogeny of the AV node, followed by an experimental (quail/chick) study postulating a new concept on the developmental origin of the AV node and in particular the slow pathway of the AV node in relation to the etiology of AV-nodal reentrant tachycardia.
In part 3 of this thesis therapeutical clinical issues in pediatric supraventricular tachycardia are outlined. Long term outcome of pediatric patients who underwent radiofrequency catheter ablation for substrates of supraventricular arrhythmias was favorable in terms of success, recurrence and complication rates.

promotie AmericaThe additive prognostic value of gated myocardial perfusion scintigraphy in patients with coronary artery disease

Yves G.C.J. America

Promotores: Prof. dr. E.E. van der Wall, Prof. dr. J.J. Bax

19 maart 2009

The main use of myocardial perfusion imaging by gated single photon emission computed tomography (SPECT) is in the assessment of the presence of reversible ischemia. As such it is used as a test to diagnose whether coronary angiography is indicated. This thesis evaluated the added prognostic value of left ventricular (LV) function parameters assessed by quantitative gated SPECT in patients with (suspected) coronary artery disease. Techniques for automated quantitative approach of myocardial perfusion imaging have been developed to minimize intra- and inter-operator variability and increase reproducibility. In a systematic analysis of all quantitative functional results provided by the Cedar-Sinai’s quantitative gated SPECT software, excellent reproducibility for LV function parameters was found. However, large perfusion defects, or the presence of spurious activity near the LV may increase operator dependence. Gated acquisition of the stress myocardial perfusion images 30 minutes post-stress reflect myocardial perfusion at maximal stress whereas LV function, which is evaluated 30-45 minutes post-stress, represents the resting situation. In patients with a previous myocardial infarction LV function post-stress may not represent true resting LV function. Left bundle branch block pattern severely reduced the diagnostic and prognostic accuracy of myocardial perfusion scintigraphy. Gated SPECT imaging may be used for stratification of candidates for revascularization as it allows the analysis of residual wall thickening in a region with a fixed perfusion defect or depressed wall motion in a region with a moderate or mild perfusion defect indicating hibernation. Gated SPECT provides important additional information beyond myocardial perfusion imaging alone, which could have major clinical implications for optimal patient management.

Promotie PundziuteImaging of coronary atherosclerosis with multi-slice computed tomography

G. Pundziūtė

Promotores: Prof. dr. J.J. Bax, Prof. dr. J.W. Jukema, Prof. dr. A. de Roos
19 maart2009

Multi-slice computed tomography (MSCT) has recently emerged as a rapidly developing non-invasive imaging modality that allows anatomical imaging of coronary arteries. In part 1 of the thesis the ability of MSCT to detect obstructive atherosclerotic lesions in coronary arteries was explored. Using conventional coronary angiography as the gold standard, the sensitivity and specificity of MSCT to demonstrate obstructive lesions on segmental level were 85% and 97%, respectively. Positive and negative predictive values were 97% and 93%, respectively. Importantly, this high diagnostic accuracy was not negatively influenced by coronary calcifications, while also good diagnostic accuracy was observed in the evaluation of coronary stents. Finally, comparison with bicycle exercise testing revealed that MSCT may provide additional information on coronary artery disease (CAD) as compared with bicycle exercise testing. Thus, 64-slice MSCT enables accurate and non-invasive evaluation of obstructive CAD. In part 2 of the thesis, MSCT was employed to characterize coronary atherosclerotic plaque extent and composition. In patients with known or suspected CAD, MSCT provided independent prognostic information over baseline clinical risk factors. Importantly, the absence of plaque was shown to indicate excellent prognosis. If compared with intravascular ultrasound (IVUS)-derived virtual histology, plaque classification on MSCT paralleled plaque composition by virtual histology. Moreover, MSCT was able to demonstrate differences in plaque characteristics in relation to clinical presentation. Thus, MSCT appears useful for coronary plaque characterization which may enhance patient risk stratification.

Promotie HuStudies on the pathophysiological aspects of the metabolic syndrome in transgenic mice

L. Hu

Promotores: Prof. dr. ir. L.M. Havekes
25 februari2009

The metabolic syndrome is a disease involving obesity, insulin resistance, dyslipidemia, hypertension, and a low-grade chronic inflammation, and is associated with high risk of cardiovascular disease. Why patients with metabolic syndrome have increased plasma levels of plasminogen activator inhibitor-1 (PAI-1) was studied in wild-type mice that were made insulin resistant by feeding a fat-rich diet, and in genetically insulin resistant mice. In both mouse models plasma PAI-1 levels are elevated, which is not due to decreased PAI-1 clearance. PAI-1 clearance was unaffected by hepatic low-density lipoprotein receptor (LDLR), nor by LDLR-related protein (LRP). However, plasma PAI-1 decay was prolonged 2-fold in mice overexpressing LDLR-associated protein (RAP).

The clearance of triglyceride-rich lipoproteins, such as very low-density lipoprotein (VLDL), in vivo depends on lipoprotein lipase activity and the non-specific receptors heparin sulfate proteoglycans and scavenger receptor-BI if the three major lipoprotein receptors, LDLR, LRP and VLDLR, are absent. In transgenic mice deficient in apoE and LDLR, macrophage LRP deletion did not affect plasma levels of cholesterol and triglycerides, but atherosclerotic lesion size had increased by 80% and lesions were of a more advanced type, compared to apoE-/- LDLR-/- mice with unmodified macrophages. These results suggest that macrophage LRP has an atheroprotective potential. In patients with metabolic syndrome increased low-grade inflammation, as reflected by increased C-reactive protein (CRP) levels, is accompanied by decreased numbers of endothelial progenitor cells and hematopoietic stem cells, and those numbers are lower in patients with atherosclerotic plaques than in patients without atherosclerotic plaques. Therefore, in patients with metabolic syndrome low-grade inflammation is associated with vascular damage and is a potential target of therapy.

Promotie HassanNovel insights in reperfusion therapy and stent thrombosis in the drug eluting stent era

A.K.M. Hassan

Promotores: Prof. dr. J.W. Jukema, Prof. dr. M.J. Schalij,
14 januari2009

Primary percutaneous coronary intervention (PPCI), usually combined with stenting, has become the standard treatment for acute ST-segment elevation myocardial infarction (STEMI). Antiplatelet agents are essential adjunctive therapies in patients with STEMI undergoing PPCI. Abciximab is an antibody directed against the glycoprotein IIb/IIIa receptor of platelets, thereby inhibiting the final common pathway of platelet aggregation. The use of abciximab as an adjunctive therapy with PPCI is recommended by current guidelines. The first aim of the thesis was to evaluate the immediate, short and long term outcomes of early abciximab administration prior to PPCI in patients suffering from acute STEMI. Patients with STEMI who had been treated with abciximab in the ambulance had, compared to patients with STEMI who were treated with abciximab upon arrival in the LUMC, 4 times higher chance to have a patent infarct-related artery, smaller enzymatic infarct size, higher left ventricular ejection fraction (LVEF) at 3 months, and lower incidence of heart failure at 7 months. The incidence of aborted myocardial infarction (MI) was 4 times higher in the pre-hospital abciximab group than in the in-hospital abciximab group. In the aborted MI group LVEF at 3 months was higher than in the established MI group, associated with superior prognosis. Peak plasma troponin T (TnT) level was correlated with enzymatic infarct size, LVEF at 3 months, incidence of cardiac complications, and incidence of heart failure at 7 months. Finally, the thesis presents a meta-analysis of late stent malapposition and (very) late stent thrombosis, when using drug eluting stents (DES) or bare metal stents (BMS). The risk of acquired late stent malapposition in patients with DES was 4.3 times higher compared to BMS when only data from randomized trials were used, and late stent malapposition was associated with 6.5 times higher risk of (very) late stent thrombosis.