Proefschriften 2013

Characterization of the right ventricle: embryonic development, noninvasive imaging andelectrocardiography

Roderick W.C. Scherptong
Promotores: Prof.dr. M.J. Schalij, Prof.dr. E.E. van der Wall
26 februari 2013

Cover ScherptongThe aim of this thesis was to further characterize the right ventricle within three different fields of cardiovascular research: 1. Embryonic development, 2: Non-invasive right ventricular imaging, 3: Right ventricular electrocardiography. In part I, several aspects of embryonic development, relevant for normal right ventricular morphology and function are investigated. In chapter 2, a novel concept for normal development of the right ventricular outflow tract is introduced. In chapter 3, the potential relevance of epicardium-derived cells for the difference between left and right ventricular morphology is discussed. Non-invasive imaging techniques are evaluated in part II. In chapter 4, the use of conventional semi-quantitative measurement of right ventricular function in patients with transposition of the great arteries is analyzed. The relevance of abnormal response to stress, measured with cardiovascular magnetic resonance imaging, is investigated in chapter 5. Chapters 6-8 demonstrate how strain measurement can be used in various types of (suspected) right ventricular disease. In part III, both conventional electrocardiography as well as computerized vectorcardiography is described in patients with right ventricular disease. A case-study of conventional electrocardiographic assessment of right ventricular pressure overload is provided in chapter 9. The prognostic value of QRS duration in patients with tetralogy of Fallot who undergo pulmonary valve replacement, is demonstrated in chapter 10. Chapter 11 and 12 discuss the application of ECG-derived vectorcardiography in normal subjects and suspected pulmonary arterial hypertension patients.

Post-interventional atherosclerotic vascular remodeling: Preclinical investigations into immune-modulatory therapies

Mark M. Ewing
Promotores: Prof.dr. P.H.A. Quax, prof.dr. J.W. Jukema
23 mei 2013

Cover EwingCardiovascular diseases remain the major cause of death throughout the world and can be primarily attributed to atherosclerotic vascular disease leading to stroke and coronary heart disease (CHD). Improved primary prevention and the introduction and subsequent optimization of percutaneous coronary interventions (PCI) for myocardial ischemia due to obstructive CHD have significantly improved patient outcome and reduced morbidity and mortality. The insight into disease pathology has however expanded tremendously over the past decade and continuing research has shifted the focus of interest towards post-interventional accelerated atherosclerosis development due to a dysfunctional (auto) immune inflammatory response, responsible for vascular remodeling, re-occlusion and recurrence of symptoms.
The aim of this thesis was to investigate the role of and intervention in the immune system in the pathophysiological process leading to the development of post-interventional atherosclerotic vascular remodeling by applying pre-clinical surgical models, which could be applied during PCI or CABG-surgery in the clinical setting.
This research was based on the fact that development of post-interventional atherosclerotic vascular remodeling can be divided into specific phases of chronic tissue inflammation elicited by the activated immune system. First, intervention for established occlusive atherosclerotic disease induces arterial injury which elicits the expression of pro-coagulant factors and arterial thrombosis. This provides the scaffold for cells and mediators from the innate immune system to undergo local adhesion, infiltration and activation into the arterial wall. Secondly, innate immune responses are directed towards (self) immunogenic molecular patterns that are present in the subendothelial space such as oxLDL particles and TLR ligands and lead to a pathological inflammatory response. Thirdly, these activated cells not only stimulate the process of vascular remodeling and matrix deposition through expression of inflammatory mediators such as cytokines, but also travel to draining lymphoid tissues to recruit residing naïve cells that belong to the adaptive immune system. To this end, intercellular communication through specific receptor-ligand interactions and co-stimulatory signals leads to activation of naïve lymphocytes that enter the circulation to engage their specific antigen-bearing targets. Their additive effects at the site of vascular injury to local infiltrated cells, antigen-antibody complexes and pro-inflammatory chemo- and cytokines promotes transcription of their inflammatory genes, enabled by tightly-controlled epigenetic regulation processes. This ultimately leads to accelerated atherosclerosis development and clinical presentation.
The important contribution of these various phases of the immune response were studied closely and this yielded multiple new promising therapeutic targets such as phosphatidylserine (PS), phosphorylcholine (PC), TLR-7 and 9, the T-cell co-stimulatory factor CTLA-4 and the epigenetic lysine acetyltransferase PCAF, as well as therapeutic applications against these targets that include annexin A5, blocking anti-PC, anti-TLR7/9 antibodies and CTLA-4 domain-containing Ig fusion proteins (abatacept). These promising anti-atherogenic applications could be introduced into the clinic within a varying range of time to be applied during PCI or CABG-surgical procedures, thus reducing vascular re-occlusions and the necessity for re-interventions.

Perspectives in the Treatment of Cardiovascular Disease: From Prognostic Parameters to Therapeutic Modalities

Surya Dharma
Promotor: Prof. dr. J.W. Jukema
29 augustus 2013

Cover - DharmaOver the last decade, a tremendous progress has been made in cardiovascular medicine [1,2]. The progress includes the treatment of coronary artery disease (CAD) and peripheral artery disease. In CAD, several advances have been made in the management of patients with acute myocardial infarction (AMI) such as: 1) the importance of networking in the treatment of AMI; 2) perspectives on how to improve the results of primary percutaneous coronary intervention (PCI) procedures including: (i) the administration of a glycoprotein IIb/IIIa inhibitor (GPI); (ii) strategies for “fighting” the coronary thrombus during primary PCI; (iii) choice of vascular access site (radial versus femoral artery approach) for primary PCI; (iv) choice of stents (drug eluting versus bare metal stent) for patients with acute ST-segment elevation myocardial infarction (STEMI); and 3) the use of intra-aortic balloon pump (IABP) in acute coronary syndrome (ACS) patients.
Another important perspective related to patients with AMI is the utilization of simple, inexpensive but accurate biomarkers with prognostic value such as plasma uric acid concentration and leukocyte count, which are particularly useful in a rural area when other established markers are not available.
Cardiovascular disease is the leading cause of mortality worldwide, including Indonesia. To decrease mortality rates, the system of care for acute myocardial infarction (AMI) patients had to be improved. The Jakarta Acute Coronary Syndrome (JAC) registry revealed that 59% of all ST-segment elevation myocardial infarction (STEMI) patients do not receive reperfusion therapy and ≈52% of these patients were referred from other hospitals. The time from onset of infarction to hospital admission was >12 hours in ≈80% of the cases. This thesis shows that, based on the characteristics of patients with acute coronary syndrome (ACS) derived from the JAC registry, implementation of a network using a pharmaco-invasive reperfusion strategy in Jakarta is feasible. This network focused on the care of AMI patients in the pre-hospital as well as in-hospital setting (Chapter 2.1).
After introduction of the network (Jakarta Cardiovascular Care Unit Network system), the implementation and effectiveness of the treatment protocol for patients with STEMI were evaluated by measuring performance indicators. Chapter 2.2 shows that after introduction of the network in 2011, STEMI patients had more inter-hospital referrals (61% vs. 56%, p<0.001) more primary percutaneous coronary intervention (PCI) procedures (83% vs. 73%, p=0.005), and more often a door-to-needle time <30 minutes (84.5% vs. 80.2%, p<0.001) than in the period 2008-2010, but numbers of patients who presented very late (>12 hours after symptom onset) were similar (53% vs. 51%). Moreover, the numbers of patients with door-to-balloon time <90 minutes and in-hospital mortality rate were similar in 2011 and in 2008-2010 (49.1% vs. 51.3%, and 8.3% vs. 6.9%, respectively). We need further improvements of the pre-hospital protocols, particularly the electrocardiogram (ECG) transmission system, and further improvements of in-hospital protocols.

Evolving imaging techniques for the assessment of cardiac structure and function and their potential clinical applications

Miriam Shanks
Promotores: Prof. dr. J.J. Bax, prof. dr. J.J. Schalij
Co-promotor: Dr. V. Delgado
5 september 2013

Cover ShanksRecent development of new techniques for quantification of tissue motion and deformation has fundamentally altered the way echocardiography approaches the characterization of global and regional myocardial function. In addition, technological progress in 3-dimensional echocardiography has made it more accessible for routine clinical use, often providing superior accuracy and reliability over 2-dimensional echocardiography. The objectives of this thesis were to study the clinical applications of the novel echocardiographic imaging modalities in the patients with cardiovascular diseases. In the first part of the thesis, evaluation of the novel parameters of myocardial function in the common cardiac conditions using 2-dimensional speckle tracking imaging and tissue Doppler imaging. In patients with ischemic heart disease, changes in the left ventricular myocardial mechanics and their incremental prognostic value for the cardiovascular outcomes are described. In addition, the mechanical properties of the left ventricle in heart failure patients, their role in predicting outcome, and their changes with therapy are explored. The second part of the thesis explores the role of the novel imaging modalities in the assessment of the cardiac anatomy and valvular function. Advanced clinical applications of 3-dimensional echocardiography in various cardiac conditions are described. The accuracy and clinical feasibility of the assessment of the mitral valve geometry from 3-dimensional images using dedicated mitral valve quantification software that is comparable to the multi-row detector cardiac tomography measurements was demonstrated. In addition, 3-dimensional echocardiography was evaluated for its accuracy for quantification of mitral regurgitation, using magnetic resonance imaging as gold standard. The role of multimodality imaging in the emerging transcatheter aortic valve implantation procedures is discussed, including its usefulness in pre-procedural screening, procedural guidance and post-procedural follow-up.

Genetic and pharmogenetic determinants of cardiovascular disease

Jeffrey J.W. Verschuren
Promotor: prof. dr. J.W. Jukema
31 oktober 2013

Cover VerschurenGenetic variation plays an important role in cardiovascular disease development. Due to the complex nature of most cardiovascular diseases, these genetic factors are part of an intricate interplay with clinical factors and environmental factors, which together determines an individual’s risk to develop a certain condition. The aim of this thesis ‘Genetic and pharmacogenetic determinants of cardiovascular disease’ was to further elucidate the genetic background of coronary restenosis and other cardiovascular diseases using large, well described study populations
We performed the very first genome-wide association study (GWAS) on restenosis in the GENetic DEterminants of Restenosis (GENDER) study population. After the GWAS analysis in GENDER, three independent replication steps were performed, leading to the identification of a novel susceptibility locus on chromosome 12. Moreover, using single nucleotide polymorphism association analysis and also using more advanced methods, like pathway analysis, we describe the association of several genes and pathways with the development of restenosis. Several of these association have not been described before and therefore could serve as a base for further research on the genetic background of restenosis.
Besides restenosis we also performed studies on other cardiovascular and vascular diseases. A possible relation of DNA repair mechanisms with the development of myocardial infarction was described. Another study explored the role of genetic variation in arteriovenous fistula failure in hemodialysis patients, a process which is thought to have overlapping underlying mechanisms with coronary restenosis.
Another subject of interest was pharmacogenetics of cardiovascular drugs. Pharmacogenetics is the upcoming field of research that examines genetic variation that influences responses to drug therapy in the individual patient. It has the very appealing goal to realize personalized therapy using genotypic guidance of pharmacotherapy by selecting agents with the greatest potential for efficacy and the least risk of toxicity. We explored previously reported associations regarding the genetic determinants of antiplatelet drug resistance in a large real‐life population of ST‐segment elevation myocardial infarction (STEMI) patients. We demonstrated that two polymorphisms, related to aspirin‐ and clopidogrel efficacy, were indeed associated with recurrent thrombotic events in this unselected patient population. These polymorphisms could therefore be of value in the identification of STEMI patients at risk for recurrent cardiovascular events.
Genetic association studies have come a long way the last decades and our understanding of the genetic background in many different diseases increased substantially. Additional studies will further expand our knowledge and could thereby aid in the development of better and more individualized treatment in the nearby future.

Cellular and molecular mechanisms of arrhythmias in cardiac fibrosis and beyond: From symptoms to substrates towards solutions

Saïd F.A. Askar
Promotor: M.J. Schalij
Co-promotor: D.A. Pijnappels
11 december 2013

Cover AskarCardiac arrhythmias are a major health concern in the western world with a rapidly increasing incidence. Although current anti-arrhythmic strategies are beneficial to patients, they can be considered suboptimal due to a largely symptomatic approach that does not fully affect the underlying pro-arrhythmic substrate. This may be explained by an incomplete understanding of the mechanisms that underlie pro-arrhythmic substrates such as cardiac fibrosis. The research described in this thesis therefore investigates cellular and molecular pro-arrhythmic mechanisms using in vitro models of such pro-arrhythmic substrates to provide and expand upon a mechanistic basis for future, more substrate-oriented anti-arrhythmic strategies. In the model of cardiac fibrosis, myofibroblasts were shown to be highly pro-arrhythmic. In a quantity-dependent manner, these cells have a detrimental depolarizing and pro-arhythmic influence on cardiac tissue, causing conduction slowing, prolongation of repolarization and ectopic activity that may give rise to reentrant tachyarrhythmias. In this thesis, it was demonstrated that by limiting proliferation of myofibroblasts, their pro-arrhythmic influence can be greatly diminished. A mechanism that appeared to be responsible for the depolarization of cardiomyocytes by myofibroblasts is heterocellular coupling, as down regulation of connexin43 expression in myofibroblasts through genetic modification had anti-arrhythmic effects. Heterocellular coupling is a pro-arrhythmic mechanism that was also observed between mesenchymal stem cells and cardiomyocytes and may therefore also have cautionary implications for the future of cardiac stem cell therapy. Through the use of genetic modification, such pro-arrhythmic mechanisms can be selectively targeted. In this thesis, control of selective transgene expression in myofibroblasts or cardiomyocytes was further refined by investigating the cellular tropism of several adeno-associated viral vectors and the use of cell type-specific promotors. By employing such genetic tools together with expanded knowledge of pro-arrhythmic mechanisms of cardiac fibrosis and other pro-arrhythmic substrates, future treatment modalities for arrhythmias may improve by becoming more mechanism- and substrate-oriented.