The objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long... Show moreThe objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long-term prognostic implications of subclinical myocardial dysfunction on all-cause mortality. Show less
Patients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to... Show morePatients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to impaired quality of life. Research is warranted to prevent progressive diabetic kidney disease, improve quality of life and reduce mortality in this vulnerable population. In order to improve survival, more knowledge about which patients have the highest mortality risk and which risk factors and co-morbid conditions contribute to this increased mortality risk is essential. In this thesis we focussed on clinical aspects of the relation between diabetes mellitus and kidney disease, from hyperfiltration to dialysis. In chapter 2 we assessed many different measures of glucose metabolism and their association with kidney function among Dutch middle-aged adults. In chapter three and four we compared survival of dialysis patients with diabetes mellitus as underlying cause of the renal failure versus dialysis patients with diabetes mellitus as a co-morbid condition only. In chapter five we aimed to develop a prediction model for 1-year mortality in diabetic dialysis patients. Furthermore in chapter six we compared survival after amputation in diabetic dialysis patients to non-diabetic dialysis patients. Show less
The comorbidities of epilepsy include those conditions, somatic and psychiatric, that are associated with epilepsy. These associations with epilepsy may be direct and indirect, causal and spurious.... Show moreThe comorbidities of epilepsy include those conditions, somatic and psychiatric, that are associated with epilepsy. These associations with epilepsy may be direct and indirect, causal and spurious. The comorbidities of epilepsy are relevant in that they provide an opportunity to improve our understanding of the pathophysiology of epilepsy, as well as allow us to better understand factors determinant of outcome. This PhD thesis examines the comorbidities of epilepsy, as a general construct, delving into particular examples, and finally demonstrating its impact on premature mortality in epilepsy. Show less
Diabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of... Show moreDiabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of functional β-cells results in the development of diabetes. Although it was previously thought that fully differentiated cells cannot change phenotype, murine studies recently indicated that mature β-cells can change identity into other islet cells under conditions of (metabolic) stress.We present a novel agarose based microwell culture system that can be used for aggregate formation of human or rodent islet cells. We show that this platform provides reproducible results to study aggregation of primary human islet cells. Using this culture system together with β-cell specific lineage tracing, we find that mature human β-cells can spontaneously lose their identity and convert into glucagon-containing α-cells. We then used human pancreatic tissue from donors with T2DM and matched controls to explore loss of β-cell identity in T2DM. We report that cells indicative of loss of β-cell identity are found more frequently in tissue samples from donors with a history of T2DM. Finally, we show that Pax4 and GLP-1 receptor agonists can partially prevent loss of identity β-cell in our ex vivo model. Show less
The objective of this dissertation was to establish the value of QCT to further enhance the clinical applicability and accuracy of coronary CTA. The automatic characterization of coronary... Show more The objective of this dissertation was to establish the value of QCT to further enhance the clinical applicability and accuracy of coronary CTA. The automatic characterization of coronary atherosclerosis with QCT is feasible and correlates well with IVUS VH. Secondly, novel CTA risk score was created incorporating detailed information on the location, severity and composition of atherosclerosis as assessed with QCT. This CTA risk score allows accurate risk stratification of patients with suspected CAD. A drawback of coronary CTA is the fact that the hemodynamic significance of a lesion cannot be evaluated. In this thesis it was demonstrated that QCT provided better correlation with the presence of myocardial ischemia on SPECT MPI as compared to current visual assessment of coronary CTA. With regards to the specific setting of high risk diabetic patients without chest pain syndrome several conclusion can be derived from this thesis. First, if treated with optimal medical therapy, very few patients present with progression of myocardial ischemia. Second, the prognosis of these patients is good; the overall long-term event-rate is limited. Especially diabetic patients without CAD on coronary CTA have an excellent prognosis. Show less
Insulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via... Show moreInsulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via increased _-cell function and/or increased _-cell mass. Inadequate _-cell adaptation leads to hyperglycemia and eventually diabetes mellitus. Therefore, it is critical to understand how the _-cell mass is regulated. We investigated _- and _-cell adaptation in response to different metabolic changes. We found that _-cell adaptation in response to insulin resistance in mice, rats, and deceased organ donors was regionally heterogeneous throughout the pancreas. We also observed that the glucagon-producing _-cell mass adapts to metabolic changes, resulting in the maintenance of the _- to _-cell ratio. Furthermore, we show that treatment of normoglycemic mice with a glucagon-like-peptide-1 receptor agonist improved _-cell function and that this is associated with a decrease in _-cell mass in order to maintain normoglycemia. In mice fed a high-fat, low-carbohydrate ketogenic diet beta-cell adaptation failed, resulting in symptoms that are associated with diabetes in humans. Finally, we developed three high-throughput culture platforms for human islets to assess _-cell function that can be used in future studies to identify novel mechanisms involved in _- and _-cell adaptation. Show less
The main objective of this thesis was to study the role of autonomic nervous system (ANS) function in the development of diabetes and cardiovascular disease using an epidemiological approach. Based... Show moreThe main objective of this thesis was to study the role of autonomic nervous system (ANS) function in the development of diabetes and cardiovascular disease using an epidemiological approach. Based on earlier studies it has remained unclear whether impaired ANS function is a risk factor for the development of diabetes and cardiovascular disease, or merely a consequence of pre-existing disease. The main conclusions of this thesis are that excess body fat, in particular visceral fat, is associated with activation of the sympathetic nervous system in individuals without diabetes and cardiovascular disease. Furthermore, this thesis showed that impaired ANS function is not a risk factor for the development of diabetes mellitus. The presented studies suggest that insulin resistance precedes the impairment of the ANS. The results from this thesis also show that impaired ANS function is a risk factor for the development of cardiovascular disease in populations without pre-existing cardiovascular disease. Furthermore, individuals with a higher heart rate have higher concentrations of cholesterol and triglycerides in the circulation and a higher intrahepatic triglyceride content, suggesting that an altered lipid metabolism may be a mechanism underlying the association between ANS function and cardiovascular disease. Show less
The aim of this thesis was to gain further insight into the role of glucagon in glucose homeostasis in healthy volunteers and type 2 diabetes mellitus (T2DM) patients, and to explore the novel... Show moreThe aim of this thesis was to gain further insight into the role of glucagon in glucose homeostasis in healthy volunteers and type 2 diabetes mellitus (T2DM) patients, and to explore the novel antisense glucagon receptor antagonist. Chapter 2 showed that the effect of meal replacers containing protein hydrolysate on plasma glucose lowering is limited in T2DM patients due to a collective increase of both insulin and glucagon levels. In chapter 3 and 4 a glucagon challenge test in healthy volunteers and T2DM was studied and showed a good reproducibility and no confounding changes in autonomic nervous system tone. T2DM patients respond profoundly different to a glucagon challenge test compared to healthy volunteers and the response to a glucagon challenge test in T2DM subjects is influenced by the type of therapy. Chapter 5 provided the first proof of pharmacology of a novel antisense glucagon receptor antagonist in humans, ISIS 325568, as reflected by a reduction in glucagon-induced glucose excursion by using a well-characterized glucagon challenge test. In chapter 6 we designed a semi-mechanistic model which simultaneously describes glucagon, plasma glucose, insulin and glucagon receptor internalization using data from glucagon challenges in healthy volunteers. Show less
Cardiovascular risk assessment in patients with diabetes mellitus (DM) remains challenging. Risk scores to predict cardiovascular risk are widely used, but are developed in the general population... Show moreCardiovascular risk assessment in patients with diabetes mellitus (DM) remains challenging. Risk scores to predict cardiovascular risk are widely used, but are developed in the general population and tend to underestimate the cardiovascular risk of DM patients. Risk scores developed in diabetic populations to estimate cardiovascular risk have demonstrated good calibration and discriminations indices. However, external validation is still needed. A recent meta-analysis showed that the predictive ability of these scores developed in diabetic populations is not superior to those scores developed in general population. Accordingly, the additional use of other biomarkers or imaging tools seems a good alternative to better risk stratify diabetic patients. This thesis evaluates the application and performance of non-invasive cardiac imaging tests for cardiovascular risk assessment and management of DM patients. Identification of new markers of CAD derived from non-invasive cardiac imaging might result in a broader applicability of cardiovascular risk assessment. Non-invasive cardiac imaging tests might evaluate target organ damage as well as the presence, severity and extent of subclinical atherosclerosis preceding overt clinical CAD. Thus, high-risk patients for CAD can be identified and further decision making of each DM patient can be tailored in order to improve the clinical outcomes at long-term follow-up Show less
Pancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor... Show morePancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor pancreata relative to the number of patients needing a transplant. The aim of this thesis was to further optimize pancreas graft survival in pancreas transplantation and to optimize islet isolation outcomes in islet of Langerhans transplantation, leading to better use of available organs. The focus in pancreas transplantation should be on optimizing recipients to improve graft survival and on improving quality of pancreata procured by centers not performing pancreas transplantation (for example, by training procurement surgeons to optimize pancreas procurement, thereby increasing the number of transplantable organs. In islets transplantation, it is recommended that the reporting of donor, pancreas and isolation factors should become more standardized, which would enable us to determine more accurately which factors are important predictors for islet isolation outcome. Furthermore, if more biomedical factors (e.g. the presence of hyperemic islets) would be reported in addition to the other factors, we would be able to assess the independent effect of these biomedical factors for islet isolation outcome and eventually the effect on islet transplantation in the clinical setting. Show less
Our studies have shown MRI assessed aortic stiffness being an integrated marker of cardiac function, cerebral small vessel disease and atrophy, as well as of renal function in type1 diabetes... Show moreOur studies have shown MRI assessed aortic stiffness being an integrated marker of cardiac function, cerebral small vessel disease and atrophy, as well as of renal function in type1 diabetes mellitus patients. Aortic stiffness already in normal range is related to end-organ damage in type1 diabetes mellitus, suggesting increased organ-susceptibility for vascular alterations in diabetes mellitus. Structural changes in the brain as a manifestation of end-organ damage has shown to be clinical relevant to elderly with diabetes mellitus predicting accelerated cognitive decline. Hypertension is a major contributor to increased aortic stiffness. There is clear effect of aortic stiffness on cardiac and cerebral end-organ damage in hypertensive patients, which is different from type1 diabetes mellitus. The results of our cross-sectional studies suggest that MRI assessment of aortic pulse wave velocity could function as a marker or risk factor for generalized vascular disease and end-organ damage that might potentially be treated. Our findings may therefore have implications for cardiovascular risk stratification and optimization of therapy in diabetes mellitus and hypertensive patients beyond classical risk factors. Finally, this thesis describes the technical implementation and benefits of right coronary artery MRA at high field 7T. This is a promising step towards improved MRI detection of coronary artery disease. Show less
In this thesis we focused on the functional and metabolic consequences of myocardial triglyceride (TG) accumulation in healthy subjects and in patients with diabetes mellitus. Ectopic accumulation... Show moreIn this thesis we focused on the functional and metabolic consequences of myocardial triglyceride (TG) accumulation in healthy subjects and in patients with diabetes mellitus. Ectopic accumulation of TGs is associated with organ dysfunction in metabolic disease in experimental animal studies. These organs include the heart, the liver and skeletal muscle. For the heart,translational studies in humans are scarce, mainly due to the difficulty of the assessment of myocardial TG content in humans, in vivo. Therefore, it remains unclear to what extent the observations in animal experiments can be extended to humans. Furthermore, the physiological and pathophysiological relevance of myocardial TG accumulation for myocardial function is unknown. In Chapter 2 we describe a non-invasive method, using hydrogen 1 magnetic resonance spectroscopy (1HMRS), to accurately and reproducibly measure myocardial TG content in humans, in vivo. We observed improved spectral resolution and an improved intraclass correlation coefficient for the assessment of myocardial TG content when spectroscopic measurements were performed with respiratory motion correction compared to spectra obtained without respiratory motion compensation. Diabetes mellitus and obesity are associated with increased plasma non-esterified fatty acid (NEFA) levels, myocardial TG accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a short-term VLCD on myocardial TG content and cardiac function in healthy subjects in Chapter 3. We found increased myocardial TG content and a decrease in left ventricular diastolic function. Moreover, hepatic TG content decreased, indicating organ-specific effects of a VLCD. In animal studies high plasma levels of NEFAs are associated with increased myocardial TG stores and impaired myocardial function. Caloric restriction increases the delivery of fatty acids to the myocardium. We have therefore evaluated the effects of progressive caloric restriction in healthy subjects in Chapter 4. Upon progressive caloric restriction we documented a dose-dependent increase in plasma levels of NEFAs and myocardial TG content, and a dose-dependent decrease in left ventricular diastolic function. Short-term high-fat diets increase TG content in skeletal muscle. Moreover, a high-fat diet induces myocardial TG accumulation and myocardial dysfunction in animal models. We studied the effects of a short-term high-fat diet in healthy individuals in Chapter 5. We found no changes in myocardial TG content and no effects on left ventricular function. However, hepatic TG content increased. The data document physiological and organ-specific adaptation of TG content during a high-fat diet. Myocardial metabolism in patients with type 2 diabetes mellitus (DM2) is heavily dependent on fatty acids. Furthermore, in animals and in humans this increased fatty acid reliability has been associated with structural changes in the diabetic myocardium and with myocardial dysfunction. Therefore we have evaluated the effects of a short-term VLCD in patients with DM2 in Chapter 6, to test the myocardial flexibility in these patients. We have shown that myocardial TGs increase after a VLCD, associated with a decrease in left ventricular diastolic function. Furthermore, anti-lipolytic therapy with acipimox during the VLCD prevented these changes in myocardial TG stores and myocardial function. Hepatic TG content was unchanged after both the interventions. The study illustrates the flexibility of myocardial TG stores and myocardial function in patients with DM2. Moreover, the data implicate the relevance of plasma NEFAs as mediators of the cardiac effects of a VLCD in patients with DM2. In Chapter 7 we evaluated the effects of therapeutic weight loss in obese, insulin-treated patients with DM2. Obesity and DM2 are major risk factors for cardiovascular disease, and prolonged caloric restriction has shown to induce weight loss and improve glycemic control. In this study we evaluated the effects of prolonged caloric restriction on myocardial and hepatic TG content and on myocardial function. Upon substantial weight loss there were considerable metabolic improvements in glucose and fat metabolism, associated with decreased myocardial TG content and a decrease in hepatic TG stores. Furthermore, myocardial diastolic function improved. The data show that in these obese patients with DM2, myocardial TG stores are flexible and amendable to therapeutic intervention by caloric restriction. Patients with type 1 diabetes mellitus (DM1) suffer from frequent episodes of hyperglycemic dysregulation, due to imperfections in exogenous insulin treatment, which mimics endogenous insulin secretion. These episodes of hyperglycemia are accompanied by perturbations in lipid metabolism as well. We have therefore evaluated the effects of controlled, short-term hyperglycemia in patients with DM1 in Chapter 8. Despite hyperglycemic dysregulation by partial insulin deprivation and the increase in plasma NEFA levels, myocardial TG content and myocardial function did not change. Apparently, the heart is protected from short-term metabolic effects of partial insulin deprivation in patients with DM1. In conclusion, myocardial TGs can be accurately measured in humans with 1HMRS. Myocardial TG stores are flexible in healthy subjects and in patients with DM2 upon differences in dietary nutritional intake. Changes in myocardial TG content are associated with changes in left ventricular function. Myocardial TGs reflect the discrepancy between fatty acid uptake and fatty acid oxidation and most likely reflect increased intracellular availability of fatty acid derivatives, which alter structure and function of the myocardium. Redistribution of TGs is tissue-specific, since TGs in the heart and the liver do not always show the same responses to physiological interventions. In patients with DM1, the heart is protected from short-term metabolic effects of hyperglycemic dysregulation, with respect to myocardial TG accumulation and alterations in myocardial function. Show less
Postnatally, Endothelial Progenitor Cells are needed to maintain the integrity of the endothelium (re-endothelialization) and to augment wound healing or vascularize hypoxic areas ... Show morePostnatally, Endothelial Progenitor Cells are needed to maintain the integrity of the endothelium (re-endothelialization) and to augment wound healing or vascularize hypoxic areas (neovascularization). Complex networks of different signals and regulators have been identified to be involved in these processes, but exact mechanisms are not completely understood. Unraveling these complex systems however would be beneficial for treatment of vascular disease. In this thesis we focus on different aspects of EPC biology. We look at the nature of these progenitor cells in a normal environment but we also look at the possible role of EPC in the pathogenesis of vascular disease in patients with Diabetes Mellitus. In both a hyperglycemic mouse model and diabetes patients we observe a reduction in circulating numbers of EPC that showed a significant inverse correlation with glycemic control. Not only did we see less EPC, we also found dysfunction of these EPC. We focus further on this dysfunction and describe mechanisms possibly involved as well as drug treatments to (partially) overcome these unfavorable effects of hyperglycemia on EPC. Eventually, we hope that these new insights in EPC dysfunction may contribute to new treatment strategies or even prevention strategies for the treatment of vascular disease in Diabetes patients. Show less
Ventricular tachyarrhythmias, the major cause of sudden unexpected cardiac arrest, occur specifically in patients with structural heart disease. In general, all types of structural heart disease... Show moreVentricular tachyarrhythmias, the major cause of sudden unexpected cardiac arrest, occur specifically in patients with structural heart disease. In general, all types of structural heart disease may lead to chronic heart failure, a severe condition with an additional high risk of atrial- and ventricular tachyarrhythmias. The thesis starts with a general overview (chapter 1) of the epidemiology, pathofysiology, prognosis and therapeutical options of heart failure. In this overview all subjects of study of the following chapters are introduced and explained. Next, attention is focused on clinical ventricular tachyarrhythmias. Chapter 2-5 of this thesis aim at evaluating the diagnostic approach, the therapeutical option of radiofrequency catheter ablation and the risk of recurrences in patients who had presented with a (malignant) ventricular tachyarrhythmia. The second part of this thesis (chapter 6-9) evaluates the effect of cardiac resynchronization therapy -a novel treatment option in patients suffering from heart failure- on the occurrence of atrial- and ventricular tachyarrhythmias. In addition the effect of cardiac resynchroniation therapy on patients with diabetes mellitus is evaluated. Show less
