This thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy... Show moreThis thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy. Additionally, predictors for a favorable outcome and important associated issues such as management and late outcome of functional mitral regurgitation and the use of LV ejection fraction as a selection criterium for indication for a implantable cardioverter defibrillator for the primary prevention ofventricular arrhythmias after surgical ventricular reconstruction were studied. In chapter 2 the early and late outcome of different types of open left ventricular reconstruction surgery by means of a meta-analysis are presented. Chapter 3 describesthe use of echocardiographic wall motion score index to predict mortality and functional results after surgical ventricular reconstruction for advanced ischemic heart failure. In chapter 4 the management of functional mitral regurgitation during left ventricular reconstruction is presented followed by a landmark analysis into the 10-year outcome of functional mitral regurgitation after left ventricular reconstruction. Chapter 5 discusses the use of the improved LV ejection fraction after SVR as an indication for a implantable cardioverter defibrillator for the primary prevention of ventricular arrhythmias after surgical ventricular reconstruction in heart failure patients. Chapter 6 discusses the early experience with a minimal-invasive hybrid transcatheter surgical ventricular reconstruction technique. First the technique of hybrid transcatheter left ventricular reconstruction is described. Followed by the preliminary results of this technique from 2 cardiac centres in the Netherland. Finally, the multicenter European results of hybrid less invasive reconstruction on clinical, functional and echocardiographic outcome are presented. Show less
The heart is innervated by the autonomic nervous system, which can be divided into sympathetic and parasympathetic parts. The balance between cardiac sympathetic and parasympathetic innervation is... Show moreThe heart is innervated by the autonomic nervous system, which can be divided into sympathetic and parasympathetic parts. The balance between cardiac sympathetic and parasympathetic innervation is critical for maintaining normal cardiac function. After myocardial infarction, sympathetic hyperinnervation has been discovered in patients as well as in animal models, which has raised growing awareness in relation to arrhythmogenesis. However the mechanism is not clear yet. In this thesis, we hypothesize a role for epicardium-derived cells (EPDCs) in this process. In addition, we aimed to study ganglia remodeling after myocardial infarction. We explored: i) the role of EPDCs in promoting cardiac sympathetic re-/hyperinnervation after cardiac damage in vitro, ii) the impact of sex of EPDCs on cardiac innervation, iii) the generation of inducible proliferative human EPDCs (iEPDCs), iv) neuronal remodeling of superior cervical ganglia after myocardial infarction and v) the molecular signature of SCG revealed by single nucleus RNA sequencing. Show less
Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and... Show moreHereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and internal bleedings. In the majority of patients mutations are found in genes belonging to the TGFβ superfamily, causing a disbalance in the TGFβ signaling pathway by haploinsufficiency of the remaining functional protein. In this thesis we studied different aims and approaches to influence HHT1-MNC homing and differentiation to restore their contribution to tissue repair. In various experimental methods inducing ischemic and/or direct tissue damage, we aimed to improve tissue repair in the Eng+/- mice. Using DPP4 inhibition, we increased the SDF1-CXCR4 homing mechanism, to restore the impaired homing capacity of the HHT1-MNCs. Furthermore, we focused on correcting the M1/M2 differentiation in Eng+/- mice. Via use of the BMP receptor inhibitor LDN we aimed to restore the skewed BMP/TGFβ signaling; stimulating the TGFβ pathway signaling to induce M2 differentiation. We concluded that DPP4 inhibition can be used to improve the HHT1 immune system and tissue repair, and is best used in concert with other drugs or therapies that stimulate cardiac or tissue repair, like anti-coagulants or cell therapy. Show less
Cardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to... Show moreCardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to investigate the role of inflammation in CVD related cardiac and vascular remodelling, which may lead to potential therapeutic agents. We investigated the therapeutic potential of antibodies directed against phosphorylcholine (PC), an endogenous ligand capable of triggering the innate immune system, which is expressed by apoptotic cells and oxidized LDL, in mouse models for myocardial infarction (MI). We found that treatment with anti-PC antibodies reduces adverse cardiac remodelling after both permanent MI as myocardial ischemia reperfusion (MI-R) injury. Furthermore, we found that treatment with annexin A5 also reduces adverse cardiac remodelling after MI-R injury. Interestingly, both anti-PC as annexin A5 treatment reduced the post MI inflammatory response. Next, we investigated the role of PCAF, an inflammatory related epigenetic factor, in vascular remodelling. We found that PCAF deficiency and treatment with a PCAF inhibitor reduces adverse vascular remodelling. Finally, we investigated the role of microRNAs, small RNA molecules that can affect expression of many different gene simultaneously, in vascular remodelling. We show that inhibition of microRNA-495 reduces adverse vascular remodelling. Show less
This thesis focuses on the potential of cell-based therapy in ischemic heart disease and the role of the inflammatory response after myocardial infarction (MI). Chapter 2 reviews the specific... Show moreThis thesis focuses on the potential of cell-based therapy in ischemic heart disease and the role of the inflammatory response after myocardial infarction (MI). Chapter 2 reviews the specific myocardial inflammatory events that occur following MI and explores the potential role of cell therapy, in specific of the mesenchymal stromal cell (MSC), to positively influence this process. In chapter 3 we studied the usefulness of a clinically relevant transient ischemia MI model in immunodeficient mice to investigate the potential of human stem cell therapy and compared this to the commonly used animal MI model via permanent ischemia. Next, in chapter 4 we aimed to extend our previous research regarding the positive therapeutic effects of MSC therapy after MI by injecting MSCs stimulated with the pro-inflammatory cytokine interferon-γ, since pro-inflammatory priming has shown additional beneficial effects in several experimental disease models. Chapter 5 evaluates the short-term effect of human cardiomyocyte progenitor cell infusion on cardiac function in an animal MI model. Chapter 6 discusses the effect of diet-induced hypercholesterolemia on both cardiac function and inflammation after myocardial ischemia-reperfusion injury. Finally, chapter 7 provides an overview of the results described in this thesis, and discusses future perspectives. Show less
Evaluation of patients with ischemic heart disease using echocardiography is indispensable. Both in the acute setting of STEMI, at follow-up and in the chronic phase during the possible development... Show moreEvaluation of patients with ischemic heart disease using echocardiography is indispensable. Both in the acute setting of STEMI, at follow-up and in the chronic phase during the possible development of heart failure, routine echocardiographic assessment is an essential part of daily clinical practice. Show less
This thesis aimed to identify possible risks associated with erythropoiesis-simulating agent (ESA) use. First, trends in anemia management are described, showing less ESA use in Swedish patients... Show moreThis thesis aimed to identify possible risks associated with erythropoiesis-simulating agent (ESA) use. First, trends in anemia management are described, showing less ESA use in Swedish patients with chronic kidney disease (CKD) and less ESA-treated patients had a hemoglobin above 12 g/dL. Furthermore it is shown that ESA- treated pre-dialysis patients in the Netherlands received more antihypertensive agents than patients without ESA, confirming the hypertensive effect of ESA. However, no relevant difference in routinely measured blood pressure was observed between patients with and without ESA treatment, thus the hypertensive effect of ESAs could be controlled in clinical practice. In addition, no excess of thrombotic events was shown in ESA-treated dialysis patients compared to patients without ESA treatment. In contrast, a higher risk of cardiovascular events with ESA use was indicated in Danish patients with multiple myeloma and myelodyslastic syndrome. Also, with two analytical approaches, a harmful effect of high ESA doses on mortality was indicated in Dutch dialysis patients. Last, it was shown that ESA resistance was associated with mortality in both hemodialysis and peritoneal dialysis patients. To conclude, treatment with high ESA doses was associated with a higher risk of mortality, but the mechanism is largely unknown. Show less
The studies in this thesis are performed to provide additional and improved insight into the effects and interplay of dietary lipids and metabolic inflammation on cardiac performance in the... Show moreThe studies in this thesis are performed to provide additional and improved insight into the effects and interplay of dietary lipids and metabolic inflammation on cardiac performance in the presence or absence of atherosclerosis and myocardial infarctions (MI). We show that high-fat diet feeding has mild but significant detrimental effects on cardiac function. In contrast to our expectations, this effect is not likely to be mediated by Toll-like receptor 2 or Toll-like receptor 4. Also, we demonstrated in mice that high-fat diet feeding does not significantly aggravate cardiac dysfunction post-MI. Deficiency of RP105, a modulator of inflammation, improved cardiac function after induction of MI. In addition, ABCA1 had adverse effects on cardiac function post-MI, possibly via a reduced activation of immune cells. This confirms the important role of inflammation in recovery after MI. Furthermore, we elucidated a possible reason for the failure of niacin in recent clinical trials and found that niacin__s anti-atherogenic properties are most potent by lowering LDL-cholesterol on top of statin treatment. Altogether, these results provide novel insights and targets for the prevention or treatment of cardiovascular diseases. Show less
Myocardial infarction and ischaemic stroke are both forms of arterial thrombosis. It is unclear to what extent hypercoagulability is a causal factor of these diseases and whether this effect might... Show moreMyocardial infarction and ischaemic stroke are both forms of arterial thrombosis. It is unclear to what extent hypercoagulability is a causal factor of these diseases and whether this effect might be different for myocardial infarction and ischaemic stroke. Several measures of hypercoagulability were investigated in the RATIO study, a nationwide population based case-control study which includes 248 women with myocardial infarction, 203 women with ischaemic stroke and 925 control women, all under 50 years of age. Chapter 2 describes the relationship of a positive family history of arterial thrombosis and the risk of either myocardial infarction or ischaemic stroke. Chapters 3-6 focus on the intrinsic coagulation proteins. Chapters 7-9 describe a genetic approach that focuses on the role of fibrinogen and coagulation factor XIII. Chapter 10 discusses the role of the fibrinolytic capacity, chapter 11 discusses VWF and ADAMTS13, and chapter 12 discusses the risk of myocardial infarction and ischaemic stroke associated with the presence of markers of the antiphospholipid syndrome. Chapter 13 provides a summary and discussion of these results. These results suggest that hypercoagulability is a cause of ischaemic stroke, whereas it does not have a major effect on the risk of myocardial infarction in young women. Show less
Cardiovascular disease are a leading cause of mortality and morbidity in the Western world. Platelets play an important role in the development of cardiovascular disease, not only in the acute... Show moreCardiovascular disease are a leading cause of mortality and morbidity in the Western world. Platelets play an important role in the development of cardiovascular disease, not only in the acute onset of thrombosis after atherosclerotic plaque rupture but also in the initiation and progression of atherosclerosis and plaque formation. In recent years, the awareness has grown that platelet function may vary among individuals and that high platelet reactivity may increase the risk of cardiovascular events. This thesis addresses variation in platelet reactivity in relation to occurrence of cardiovascular events. We show that high platelet reactivity in subjects with cardiovascular disease using aspirin or clopidogrel as well as in antiplatelet drug-na_ve healthy subjects is related to the risk of cardiovascular events. We also revealed several genetic and clinical risk factors of high platelet reactivity. Moreover, we show that the 110-year old antiplatelet drug aspirin has interesting time-dependent pleiotropic effects on various pressor systems underlying blood pressure. As discussed in this thesis, although promising results have been published, routine platelet reactivity testing in daily clinical practice would currently be premature. Future studies are warranted to further investigate the clinical applicability of platelet reactivity testing in subjects at risk for cardiovascular events. Show less
Stem cell therapy has raised enthusiasm as a potential treatment for cardiovascular diseases. However, questions remain about the in vivo behavior of the cells after transplantation and the... Show moreStem cell therapy has raised enthusiasm as a potential treatment for cardiovascular diseases. However, questions remain about the in vivo behavior of the cells after transplantation and the mechanism of action with which the cells could potentially alleviate disease symptoms. The objective of the research as described in this thesis was to visualize survival, proliferation, and migration of embryonic (ESC) and adult stem cells using non-invasive molecular imaging techniques in small animal models of cardiovascular diseases. The major findings can be described as follows: (1) Non-invasive bioluminescence imaging is a validated tool to monitor donor cell survival, proliferation, migration, and misbehavior; (2) ESC are a potential source for true regenerative therapy; (3) ESC form teratomas; (4) Adult stem cell survival is short-lived, but of all cells currently used in the clinic, mononuclear cells show the most prolonged survival; (5) Transplantation of mononuclear cells can preserve cardiac function in the short term after myocardial infarction in mice; (6) Compared to other measurements of murine cardiac function, Micro-CT is a superior method to assess cardiac geometry and function; and (7) Transplantation of mononuclear cells in peripheral artery disease is hampered by dismal cell survival and homing. These findings illustrate the current challenges for optimizing stem cell therapy for cardiovascular disease. Show less
The presence of a decreased left ventricular (LV) function after myocardial infarction has demonstrated to be of considerable clinical importance. In this thesis, the role of 2D echocardiography to... Show moreThe presence of a decreased left ventricular (LV) function after myocardial infarction has demonstrated to be of considerable clinical importance. In this thesis, the role of 2D echocardiography to evaluate LV function in ischemic heart disease was investigated. In the first part of the thesis, recently introduced echocardiographic parameters to describe LV function were studied and their importance for prognosis after myocardial infarction was evaluated. In addition, in the second part of the thesis, the role for echocardiography in the decision making around advanced treatment options in heart failure such as cardiac resynchronization therapy (CRT) and cardiac surgery was explored. Show less
Embryonic EPDCs are crucial for proper myocardial architecture and coronary vessel formation, both through their physical contribution and their regulatory role in these developmental processes.... Show moreEmbryonic EPDCs are crucial for proper myocardial architecture and coronary vessel formation, both through their physical contribution and their regulatory role in these developmental processes. This thesis reports for the first time on the role of Epicardium-Derived Cells (EPDCs) in the adult ischemic heart. It is demonstrated that transplanted adult EPDCs, isolated from human adult epicardial tissue, improve left ventricular function of the ischemic mouse heart. This is probably instigated by an early paracrine-mediated stimulation of the injected EPDCs on the surrounding host tissue, as indicated by increased wall thickness, augmented vascular density (mouse origin), and enhanced DNA-damage repair activity of the endogenous tissue. Cardiac healing in the EPDC-recipients is further characterized by advanced WT-1 expression, a marker for undifferentiated EPDCs, indicating induction of endogenous epicardial activity. Strikingly, the benefit of EPDC injection can be further enhanced by adding complementary cardiomyocyte progenitor cells to the EPDC transplant, explained by synergistic paracrine actions of the two different cell types. Two different techniques for assessment of left ventricular function in the post-infarct failing mouse heart are evaluated. It is shown that both conductance catheter and magnetic resonance imaging are reliable methods, each having specific unique features which need to be considered during experimental set-up. Show less
While currently available therapeutic options for the treatment of acute myocardial infarction are sufficient for the treatment of symptoms, the underlying causes usually remain unresolved, being... Show moreWhile currently available therapeutic options for the treatment of acute myocardial infarction are sufficient for the treatment of symptoms, the underlying causes usually remain unresolved, being loss of electrically active, contractile, myocardial tissue. Recently, extensive research has been performed in the field of cell and gene therapy. The ultimate aim of these therapies is to __heal__ the infarcted area on a more biological basis, by repopulating the damaged area with __new__ cells that contribute to proper cardiac function, including electrical activation of the myocardium. In order to comprehend the potential therapeutic value and hazard of cell modification and transplantation for ischemic heart diseases, one should consider the heart as a highly integrative, electromechanical organ. Therefore, 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 cure the damaged, ischemic heart. Show less
Given their self-renewing and pluripotent capabilities, embryonic stem cells (ESCs) are well-poised as a cellular source for tissue regeneration therapy. Successful in vitro differentiation of both... Show moreGiven their self-renewing and pluripotent capabilities, embryonic stem cells (ESCs) are well-poised as a cellular source for tissue regeneration therapy. Successful in vitro differentiation of both mouse (m) and human (h) ESCs into multiple somatic cell types has been reported, including cardiomyocytes, neurons and pancreatic islet cells. However, the host immune response against transplanted ESCs is not well characterized. In fact, controversy remains as to whether ESCs have immune-privileged properties. The scope of the current thesis is to gain insight into immunological aspects of transplantation of embryonic stem cells or their differentiated progeny by using molecular imaging techniques to follow cell fate. Specifically, this thesis presents evidence that: (1) molecular imaging can be used to quantify organ and ESC survival following transplantation and non-invasively follow donor graft fate; (2) ESCs express MHC and co-signaling molecules that are upregulated upon differentiation; (3) mESCs and hESCs can trigger potent cellular and humoral immune responses following allogeneic and/or xenogeneic transplantation, leading to rejection; and (4) immunosuppressive drugs can significantly mitigate the host immune response to prolong hESC survival in immunocompetent mice. These results clearly indicate that ESC immunogenicity is a significant hurdle that must be overcome before successful clinical application can be accomplished. Show less
Measurement of quality of life (QOL) as an indicator of health outcome has become increasingly important in patients with coronary artery disease. Nitrates can effectively control symptoms of... Show moreMeasurement of quality of life (QOL) as an indicator of health outcome has become increasingly important in patients with coronary artery disease. Nitrates can effectively control symptoms of angina. A once daily dosage regimen of isosorbide mononitrate might provide better QOL than conventional multiple daily dosage regimen. To assess this, we performed two studies in patients with angina pectoris. We conclude that replacement of a multiple daily dosage regimen with a once daily dosage regimen results in an improved QOL, anginal NYHA class and exercise capacity. We also conclude that patients with certain cardiac risk factors and co-morbidities might particularly benefit. In a separate chapter we study the influence of pschychological factors on QOL in patients with heart failure and in patients on the waiting list for coronary angiography. Finale we discuss a study concerning early discharge in patients with acute myocardial infarction treated with primary PCI. We conclude that hospital discharge on the day after admission in combination with a rehabilitation program is feasible and offers a safe and patient-friendly alternative to the usual 3 to 4 days of in hospital care, without negative effect on QOL or secondary prevention goals. Show less
Vascular maladaptation prior and during implantation may lead to serious complications during pregnancy, perinatally, but also later in life (Barker hypothesis). The consequences later in life... Show moreVascular maladaptation prior and during implantation may lead to serious complications during pregnancy, perinatally, but also later in life (Barker hypothesis). The consequences later in life often appear to be related to endothelial dysfunction. Angiogenesis, the formation of new blood vessels from pre-existing ones, is an important endothelial function and plays a key role in the process of implantation and placentation. Two epidemiological studies described here, show that myocardial infarction is related to low birth weight and that assisted procreation adversely affects birth weight. An optimal intra-uterine environment forms the basis for a good perinatal outcome and is created by a receptive endometrium in which angiogenesis is crucial. To study endometrial angiogenesis, human endometrial endothelial cells were isolated. The high expression of u-PA by these cells was found to contribute to their high angiogenic properties. Furthermore, these cells depend on MT3-MMP to form tubes. The ovarian steroids overall regulate endometrial angiogenesis indirectly via the endometrial stromal cells. During implantation, the embryo takes over as the main (local) regulator by inducing angiogenesis at its implantation site through the expression of VEGF. These results provide more insight in the (patho-)physiology of endometrial angiogenesis and in the role of the embryo in this. Show less
