Background: Persistent dyspnea and reduced exercise capacity is common in pulmonary embolism (PE) survivors. Although improved right ventricular function after pulmonary rehabilitation has been... Show moreBackground: Persistent dyspnea and reduced exercise capacity is common in pulmonary embolism (PE) survivors. Although improved right ventricular function after pulmonary rehabilitation has been demonstrated in chronic thromboembolic pulmonary hypertension, it is still unknown whether a similar effect also occurs in other patients with dyspnea after pulmonary embolism. Purpose: The aim of this study was to explore potential effects of a pulmonary rehabilitation program on cardiac structure and function as assessed with cardiac magnetic resonance (CMR). Material and methods: Twenty-six PE survivors with persistent dyspnea were included. Right and left ventricular assessment with CMR was performed before and after an eight-week pulmonary rehabilitation program. Results: Dyspnea as measured by the Shortness of Breath Questionnaire improved significantly after rehabilitation: 15 (IQR: 7-31) versus 8 (IQR: 3-17). Absolute right ventricular global longitudinal strain by CMR was reduced from 19% to 18% (95% CI of difference: 0-3 percent points), and absolute RV lateral strain from 26% to 24% (95% CI of difference: 1-4 percent points). Right ventricular mass was reduced after rehabilitation from 49 g to 44 g (95% CI of difference: 2-8 g). Conclusion: Although there was a substantial improvement in dyspnea after rehabilitation, we found only a minor reduction in absolute right ventricular longitudinal strain and right ventricular mass. No other CMR parameter changed. We therefore suggest that rehabilitation effect of in this patient group was not primarily mediated by cardiac adaptions. Show less
Studying diseases or effects of new drugs on the human body is challenging, not least because of the lack of proper testing models that recapitulate human physiology. Most research is done using... Show moreStudying diseases or effects of new drugs on the human body is challenging, not least because of the lack of proper testing models that recapitulate human physiology. Most research is done using animal models but these often show differences with humans in disease manifestation and responses to drugs. For example, drugs that had no effect on the hearts of animals later turned out to cause lethal arrhythmias in some humans. This – and the ethical issues around animal testing – is why, as in this thesis, there is increasing interest on making human heart models based on pluripotent stem cells (hPSCs). Nowadays small numbers of cells can be collected from a patient (e.g. from blood, urine or skin), reprogrammed to hiPSCs, and then differentiated to heart muscle cells (cardiomyocytes). Since the genetics of the patient are maintained during reprogramming, the phenotype of a genetic disease affecting cardiac function can also be captured. The focus of this thesis has been developing methods to measure these cardiac phenotypes robustly and with sufficient complexity to reflects drug responses and disease of the heart. Our results supported the notion that hPSC models will become human avatars and accurate measurement models able to recapitulate essential human-specific processes. Show less
Duchenne muscular dystrophy is a severe muscle wasting disease, characterized by a severely reduced lifespan in which cardiomyopathy is one of the leading causes of death. Multiple therapies aiming... Show moreDuchenne muscular dystrophy is a severe muscle wasting disease, characterized by a severely reduced lifespan in which cardiomyopathy is one of the leading causes of death. Multiple therapies aiming at dystrophin restoration have been approved. It is anticipated that these therapies will maintain muscle function for longer and extend the ambulatory period, which in turn will increase the cardiac workload which could be detrimental for cardiac function. We investigated the effects of voluntary running exercise in combination with low dystrophin levels on function and pathology of skeletal muscle and heart. We divided 15.5-month old female mdx (no dystrophin), mdx-Xist(Delta hs) (varying low dystrophin levels) and wild type mice (BL10-WT and Xist(Delta hs)-WT) to either a sedentary or voluntary wheel running regime and assessed muscle function at 17.5 months of age. Thereafter, a cardiac MRI was obtained, and muscle and heart histopathology were assessed. We show that voluntary exercise is beneficial to skeletal muscle and heart function in dystrophic mice while not affecting muscle pathology. Low amounts of dystrophin further improve skeletal muscle and cardiac function. These findings suggest that voluntary exercise may be beneficial for skeletal muscle and heart in DMD patients, especially in conjunction with low amounts of dystrophin. Show less
The epicardium has been identified as a potential source of cardiac progenitors, however, the exact contribution during regeneration is still under debate. The aim of this thesis is to gain... Show moreThe epicardium has been identified as a potential source of cardiac progenitors, however, the exact contribution during regeneration is still under debate. The aim of this thesis is to gain more insight of the involvement of WT1 and the epicardium in the cellular and molecular processes of the developing heart and after cardiac injury. In Chapter 2, the spatiotemporal expression pattern of WT1 during developmental stages and after cardiac injury in mice and a potential role for WT1 in cardiac endothelial cell proliferation and vessel formation are described. Chapter 3, shows that the expression of WT1 is present during human cardiac development in cells that are crucial for the formation of the cardiac vessels and ventricular myocardium. Chapter 4 is a comprehensive book chapter about the role of WT1 in cardiac development and after injury. In Chapter 5, we investigated the development of the epicardium in relation to cardiac innervation and we show for the first time that the epicardium plays a role in modulating the cardiac autonomic response prior to innervation. In Chapter 6, the response of EPDCs to mechanical stimulation has been studied by transplantation of EPDCs in infarcted myocardium and by using an in vitro straining device. Show less
Research described in this thesis is based on clinical data obtained through diabetes cardiovascular risk management (DIACARM) project. A clinical protocol founded on the co-operation of the... Show moreResearch described in this thesis is based on clinical data obtained through diabetes cardiovascular risk management (DIACARM) project. A clinical protocol founded on the co-operation of the departments of endocrinology, cardiology, nephrology, radiology and nuclear medicine at the Leiden University Medical Center. This protocol is set to improve medical care at patient and provide more insight into cardiovascular risk stratification in asymptomatic patients with diabetes. The first part of the thesis focuses on the nature of coronary artery disease in diabetes, and its presentation with different imaging modalities. The relation between epicardial adipose tissue and plasma biomarkers with coronary atherosclerosis were investigated. Furthermore, extent and morphology of atherosclerosis are compared in patients with type 1- and type 2 diabetes. In the second part of the thesis the value of non-invasive vascular measurements (carotid intima media thickness, pulse wave velocity) and cardiac imaging techniques were evaluated and compared for risk stratification of coronary artery disease in diabetes. The final part of the thesis describes a novel technique, sidestream dark field imaging, for the assessment of the microcirculation at capillary level. Parameters of microcirculation were shown to have a relation with coronary artery disease in diabetes Show less
To treat various cardiac diseases, modification of gene expression for the purpose of increased or decreased expression of a particular gene, is regarded as a potential therapy. As a vehicle to... Show moreTo treat various cardiac diseases, modification of gene expression for the purpose of increased or decreased expression of a particular gene, is regarded as a potential therapy. As a vehicle to introduce the gene of choice into the heart cell, virus vectors have given the most promising results. This thesis describes studies that are undertaken to investigate how virus vectors may be used to efficiently target cardiac cells and what the effects of certain genetic interventions are on the (patho)physiology of heart cells. We used lentivirus vectors to study the effects of integrin stimulation in neonatal rat cardiomyocytes on the uptake of macromolecules by these cells and through which pathway integrin stimulation leads to cardiac hypertrophy. Furthermore, the role of gap junctional coupling in the development of arrhythmias and in the cardiac differentiation of mesenchymal stem cells was investigated by modulating the expression of connexin 43 using lentivirus vectors. As adeno-associated virus vectors in particular have shown great potential as vector system to target the heart, we aimed to develop AAV vectors that may be used to specifically target either the cardiomyocytes or fibroblasts in the heart. Show less
Injection of (stem) cells into the damaged heart has a positive effect on cardiac function. In this thesis two strategies for improving myocardial regeneration over classical cell therapy were... Show moreInjection of (stem) cells into the damaged heart has a positive effect on cardiac function. In this thesis two strategies for improving myocardial regeneration over classical cell therapy were investigated. The first is to induce cardiomyogenic differentiation by genetically engineering cells to express the transcription factor myocardin (a regulator of cardiomyocyte differentiation). We found that overexpression of myocardin induces a large part of the cardiac muscle gene expression program in various non-muscle cells. Forced expression of myocardin enables cardiac infarction scar fibroblasts to conduct a cardiac action potential, and injection of myocardin-transduced MSCs resulted in greater preservation of cardiac function and reduced detrimental remodeling compared to untreated MSCs in a mouse model of myocardial infarction. Indicating that overexpression of myocardin endows cells with several beneficial properties of cardiomyocytes. We hypothesized that myocardial regeneration might be enhanced by including novel cell types with supportive functions in cell therapy strategies. We found that the mesothelial cells of the human epicardium, like embryonic epicardium-derived cells (EPDCs) can form fibroblasts and smooth muscle cells. Indicating that EPDCs from human adults recapitulate at least part of the differentiation potential of their embryonic counterparts, which form various essential supportive cell types during heart development. Show less
We have developed several methods for automated analysis of echocardiographic images. This thesis describes these methods and their evaluation and use. It is shown that semiautomatic detection... Show moreWe have developed several methods for automated analysis of echocardiographic images. This thesis describes these methods and their evaluation and use. It is shown that semiautomatic detection based on Dynamic Programming and Pattern Matching provides a useful and reliable way of analyzing 2D echocardiographic sequences of different cross sections. Main conclusion is that the new detection tools based on statistical models (Active Appearance Models) provide superior possibilities for automated analysis of echocardiographic images, since they are capable of realistically modeling both the typical problems and artifacts of cardiac ultrasound and the variability between patients. Also, these tools can be extended towards multi-view and multi-stage applications (e.g. stress echo), higher dimensions (3D echo), and simultaneous detection of multiple structures (LV, RV, atria, epicardium, valves). They also offer possibilities for computer-aided diagnosis, such as wall motion abnormality classification (stress echo and Cardiac Resynchronization Therapy). Further development and integration with other border detection and tracking approaches is certainly feasible and will offer a range of new research opportunities. The difficulties have not yet been completely overcome, but we are confident that fully automated, reliable analysis of echocardiographic images will eventually become a definite reality. Show less
