With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
Osteoarthritis is one of the most common musculoskeletal disorders. Despite its high prevalence, the pathogenesis of osteoarthritis is incompletely understood. A major risk factor for... Show moreOsteoarthritis is one of the most common musculoskeletal disorders. Despite its high prevalence, the pathogenesis of osteoarthritis is incompletely understood. A major risk factor for osteoarthritis is obesity. Not only due to increased mechanical stress, but also due to systemic factors such as lipids. Our knowledge on how lipids are involved in osteoarthritis is limited. Therefore, this thesis focusses on the association of lipids with hand and knee osteoarthritis. Firstly, we investigated the reproducibility of lipid measurements to guide future lipidomic research. Subsequently, comparison of the lipid profile of osteoarthritis patients in different disease stages showed that the lipid profile explained disease severity to a limited extent. We observed the strongest association of the lipid profile with hand pain, and no association with knee osteoarthritis. This suggests that lipotoxicity may play a larger role in the hand, while in the knee mechanical stress is more relevant. In addition, treatment with anti-inflammatory medication resulted in a change in lipid concentrations in patients with hand osteoarthritis, suggesting that lipids are involved in inflammation and/or pain processes. These insights may increase our understanding of osteoarthritis pathophysiology and lead to new targets for future development of disease modifying osteoarthritis medication. Show less
OBJECTIVES: The objective was to analyse associations between obesity and outcomes after left ventricular assist device (LVAD) implantation.METHODS: A retrospective analysis of the EUROMACS... Show moreOBJECTIVES: The objective was to analyse associations between obesity and outcomes after left ventricular assist device (LVAD) implantation.METHODS: A retrospective analysis of the EUROMACS Registry was performed. Adult patients undergoing primary implantation of a continuous-flow LVAD between 2006 and 2019 were included (Medtronic HeartWare((R)) HVAD((R)), Abbott HeartMate II (R), Abbott HeartMate 3 (TM)). Patients were classified into 4 different groups according to body mass index at the time of surgery (body mass index <20 kg/m(2): n = 254; 20-24.9 kg/m(2): n = 1281; 25-29.9 kg/m(2): n = 1238; >= 30 kg/m(2): n = 691).RESULTS: The study cohort was comprised of 3464 patients. Multivariable Cox proportional cause-specific hazards regression analysis demonstrated that obesity (body mass index >= 30 kg/m(2)) was independently associated with significantly increased risk of mortality (body mass index >= 30 vs 20-24.9 kg/m(2): hazard ratio 1.36, 95% confidence interval 1.18-1.57, overall P < 0.001). Moreover, obesity was associated with significantly increased risk of infection and driveline infection. The probability to undergo heart transplantation was significantly decreased in obese patients (body mass index >= 30 vs 20-24.9 kg/m(2): hazard ratio 0.59, 95% confidence interval 0.48-0.74, overall P < 0.001).CONCLUSIONS: Obesity at the time of LVAD implantation is associated with significantly higher mortality and increased risk of infection as well as driveline infection. The probability to undergo heart transplantation is significantly decreased. These aspects should be considered when devising a treatment strategy before surgery. Show less
The aim of this thesis was to study the cardiometabolic consequences of obesity and weight gain during the life course. We investigated the association between body mass index (BMI) and... Show moreThe aim of this thesis was to study the cardiometabolic consequences of obesity and weight gain during the life course. We investigated the association between body mass index (BMI) and cardiometabolic disease using Mendelian randomization. We observed that all BMI-associated gene sets, grouped based on tissue expression, were similarly associated with increased risks of cardiometabolic disease. We observed that abdominal adiposity in adolescence was associated with early changes in metabolomic measures indicative of an atherogenic profile already present in young men. Weight gain during adulthood was specifically related to an atherogenic metabolic profile, in addition to increased adipocyte size. Adult weight gain between age 20 years and middle age was associated with increased visceral and liver fat at middle age. Additionally, the association between adult weight gain and insulin resistance at middle age was partly mediated by increased levels of visceral and liver fat at middle age. Lastly, we observed that a favourable body fat distribution as well as metabolic profile are associated with a decreased risk of incident cardiometabolic disease in a population with obesity. Overall, the results of this thesis emphasize the importance of maintaining a stable body weight during young adulthood throughout middle age. Show less
Overweight and obesity are abnormal or excessive body fat accumulation that presents a risk to health. The World Health Organisation defines overweight and obesity with the Body Mass Index (BMI)... Show moreOverweight and obesity are abnormal or excessive body fat accumulation that presents a risk to health. The World Health Organisation defines overweight and obesity with the Body Mass Index (BMI) classification, which is a measure of a person’s weight in kilograms (kg) divided by the square of height in meters (m2). Overweight is defined as a BMI of 25 kg/m2 or higher, whereas obesity is defined as a BMI of 30 kg/m2 or higher. It is estimated that one of every three individuals in the global population has overweight. The prevalence of obesity is increased threefold from 1975 to 2016, with a faster-growing pace in low- and middle-income countries than high-income countries. One common complication of obesity is the metabolic syndrome, which is defined as the co-occurrence of at least three out of five cardiometabolic abnormalities (abdominal obesity, hypertension, hyperglycaemia, hypertriglyceridemia, and low HDL-cholesterol). The metabolic syndrome is a strong risk factor for type 2 diabetes and cardiovascular diseases, and is considered a pathway from obesity to the cardiometabolic diseases occurrence. Thus, if metabolic syndrome or its components are identified and treated early, type 2 diabetes and cardiovascular diseases may be prevented. In this multi-ethnic global population, it is well-established that different ethnic populations have different cardiometabolic risks. Studies have shown that Asian populations develop cardiometabolic complications earlier at the same amount of adiposity as the Western populations. Show less
The overall aim of this thesis was to gain a clearer picture of the prevalence of food insecurity in the Netherlands and its consequences for dietary quality and health. The studies included in... Show moreThe overall aim of this thesis was to gain a clearer picture of the prevalence of food insecurity in the Netherlands and its consequences for dietary quality and health. The studies included in this thesis provide potential targets for interventions aimed at reducing food insecurity among affected people and families in the Netherlands.Based on this thesis, we can conclude that a considerable number of people in the Netherlands experience food insecurity. The findings described in this thesis provide insight into the consequences: food insecurity is associated with obesity, poor physical and mental health, and poor dietary quality. Our results also illuminate the role of sociodemographic and lifestyle factors, psychosocial factors and the food environment in these associations. In addition, our findings offer a clearer understanding of the perceived needs, perceptions and barriers regarding healthy eating among people at risk of experiencing food insecurity, as well as suggesting potential interventions. This thesis has shown that the issue of food insecurity needs to be better recognized and addressed in the Netherlands, for example through the development and implementation of population-based and risk group-based interventions for which appropriate screening and targeted interventions should be further explored. Show less
Stress, obesity and (stress-related) mood disorders such as depression and anxiety disorders are highly prevalent in modern society. These diseases often coincide. This may be because they trigger... Show moreStress, obesity and (stress-related) mood disorders such as depression and anxiety disorders are highly prevalent in modern society. These diseases often coincide. This may be because they trigger and reinforce each other, creating a vicious cycle. Social and psychological factors play a role in this cycle, but in this thesis we focused on the underlying biological mechanisms. We identified new obesity-related factors that likely affect fear and discovered new sites of action in the brain for factors that are already known to regulate fear. We also applied three novel drug treatment strategies. Each of these target (different) components of the stress system and were shown to alleviate stress- or diet-induced metabolic disease in mice. Certain strategies reduced obesity, while others seemed to prevent or even cure fatty liver disease in mice. This thesis thus represents a step towards breaking the vicious cycle between stress, obesity and (stress-related) mood disorders. Show less
Our increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher... Show moreOur increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher availability and intake of food, which often appears unhealthy, and lower energy expenditure related to a sedentary lifestyle. Although the most efficient ways to slow this high prevalence of obesity are just eating less and more healthy, and moving more, to reduce energy intake and increase energy expenditure, respectively, current strategies to achieve this in the long-term are still both insufficient and ineffective, and novel strategies are still eagerly warranted.This thesis emphasizes dietary butyrate as a promising and feasible therapeutic strategy to combat obesity and related cardiometabolic diseases with respect to not only reducing appetite but also activating brown adipose tissue. In a series of subsequent mechanistic studies, we elucidated the mechanisms underlying these metabolic properties systematically from gut to the brain, showing the involvement of gut microbiota, intestinal GLP-1 secretion, vagal nerve activation, and finally central GLP-1 receptor signaling to inhibit NPY neuronal activation. The findings of this thesis provide valuable information on the development of novel therapeutic strategies for combating obesity and associated cardiometabolic diseases. Show less
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
The research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in... Show moreThe research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in depth characterization of lysosome function in health and disease. An integrative approach was used to study the physiological role of the lysosome, characterizing the function of lysosomal hydrolases and signalling on a cellular level as well as within the context of tissue. Show less
Type 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op... Show moreType 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op deze ziekten. Dit komt gedeeltelijk door hun ongunstige lichaamssamenstelling met veel buikvet en vetopslag in organen zoals spieren en lever, wat hun werking verstoort. Het verminderen van overgewicht verlaagt het risico op type 2 diabetes en hart- en vaatziekten. Verminderen van voedselinname en verhogen van het energieverbruik kan hieraan bijdragen. Een veelbelovende aanpak om het energieverbruik te verhogen, is het stimuleren van vet- en suikerverbranding door lichaamseigen bruin vetweefsel. In dit proefschrift onderzochten wij eerst mechanismen die bijdragen aan cardiometabole ziekten in Zuid-Aziaten. Wij observeerden verminderde Wnt signaaltransductie in wit vet van Zuid-Aziaten, wat samenhing met minder insulinegevoeligheid in dit weefsel. Ook vonden wij een andere samenstelling van LDL-deeltjes in Zuid-Aziaten, wat samenhing met een verhoogde neiging van deze deeltjes om samen te klonteren. Daarna onderzochten wij de effectiviteit van geneesmiddelen om bruin vet activiteit te verhogen en de cardiometabole gezondheid te verbeteren. Wij lieten zien dat stimuleren van de beta-adrenerge receptor de stofwisseling verhoogt en vetverbranding door bruin vet stimuleert, echter niet méer dan koudeblootstelling. Ook vonden wij dat GLP-1 receptoragonisme de suikeropname door bruin vet stimuleert, wat mogelijk bijdraagt aan een gunstig effect op het lichaamsgewicht en suiker- en vetstofwisseling. Deze studies hebben bijgedragen aan kennis over risicofactoren voor cardiometabole ziekten en de ontwikkeling van nieuwe therapeutische strategieën om deze ziekten tegen te gaan, vooral in Zuid-Aziaten. Show less
The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
In this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss... Show moreIn this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss interventions in obese asthmatics, we defined the following aimsfor this thesis:1. To gain insight in the effects of exercise training in obese asthmatics and to determine the feasibility and effects of high intensity training in obese subjects2. To design a pulmonary rehabilitation program for obese patients with suboptimalcontrolled asthma and to determine the effectiveness of this program in a randomized controlled trial3. To improve our knowledge on the pathophysiology of obesity related asthma4. To gain insight in the risks and long-term effects of bariatric surgery in morbidlyobese subjects with asthma. Show less
Over the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart... Show moreOver the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart failure and coronary artery disease. Despite remarkable advances in cardiovascular prevention and treatment, heart disease remains a common cause of death and an important contributor to health loss. The aim of this thesis was to characterize cardiovascular remodeling associated with metabolic disturbances, using a variety of magnetic resonance techniques. This thesis demonstrates that reduced diastolic function is a common characteristic of myocardial remodeling in type 2 diabetes and obesity, but also a potential marker for the detection of patients at increased cardiovascular risk after hematopoietic stem cell transplantation and possibly a contributing factor in the pathogenesis of ventricular arrhythmia after myocardial infarction. Also, in this thesis, it was shown that the evaluation of visceral adiposity and myocardial triglyceride content may help to identify distinct cardiometabolic phenotypes and to better understand the cardiometabolic actions of the glucagon-like peptide 1 receptor agonist liraglutide. With the emergence of non-contrast cardiovascular protocols, magnetic resonance techniques may be increasingly used for cardiometabolic phenotyping in population-based cohorts as well as clinical studies. Show less
The aim of this thesis was to evaluate quantitative MRI techniques in reno-cardiovascular health, and to study the links between obesity and reno-cardiovascular health using quantitative MRI... Show moreThe aim of this thesis was to evaluate quantitative MRI techniques in reno-cardiovascular health, and to study the links between obesity and reno-cardiovascular health using quantitative MRI metrics. Furthermore, we aimed to address novel insights on the safety of contrast media with regard to the use of gadolinium. The general introduction (Chapter 1) of this thesis introduces the concept of quantitative MRI, its application in epidemiological research, reno-cardiovascular health, and in obesity. In addition, the general introduction addresses the safety of gadolinium as an MRI contrast agent. Following the general introduction a review of the clinical application and technical considerations of quantitative MRI using T1 and T2(*) mapping in cardiac and renal imaging was provided in Chapter 2. Part 1 of this thesis focused on the reproducibility and clinical validity of T1 mapping and proton magnetic resonance spectroscopy (1H-MRS) in renal imaging. Part 2, described different studies evaluating the association between obesity and reno-cardiovascular function which was analyzed in population-based imaging studies using different quantitative MRI metrics. Part 3, provides an overview of the safety profile of gadolinium containing contrast agents, and reflection on the recent EMA recommendations. Show less
The prevalence of obesity is increasing worldwide. In particular abdominal obesity is a well-established risk factor for cardiometabolic diseases. The excess risk of abdominal obesity is due to fat... Show moreThe prevalence of obesity is increasing worldwide. In particular abdominal obesity is a well-established risk factor for cardiometabolic diseases. The excess risk of abdominal obesity is due to fat in the visceral area and in and around the organs (ectopic fat), such as in the liver. The main aim of this thesis was therefore to study whether lifestyle can reduce the amount of visceral fat and liver fat.Firstly, in a systematic review and meta-analysis of randomized controlled trials, we concluded that a diet high in proteins decreases liver fat compared with a diet high in carbohydrates. A diet high in fat did not lead to changes in liver fat compared with a diet high in carbohydrates. Within fat types, saturated fat leads to more liver fat accumulation than unsaturated fat. Secondly, we studied diet at multiple levels in the Netherlands Epidemiology of Obesity study, which is a population based cohort study of middle-aged men and women with directly assessed measured of adiposity. When studying food groups rather than nutrients, we observed that consumption of sweet snacks are positively associated with liver fat content, also after taking into account total body fat. Likewise, consumption of fruit and vegetables and plant-based fats and oils was associated with less visceral fat. A better adherence to the current Dutch dietary guidelines, as indicated by a higher score on the 15-component Dutch Healthy Diet Index, was associated with less total body fat, less visceral fat and liver fat. The associations with visceral fat and liver fat remained present after taking into account total body fat, indicating that the associations are indeed specific for visceral and liver fat rather than merely representing associations with overall adiposity. Associations were not driven by one component in particular, indicating the importance of an overall healthy diet. When we studied alcohol intake separately, each additional serving of alcoholic beverages per day was also associated with more liver fat. Moreover, replacing one alcoholic serving with one non-alcoholic serving was associated with less liver fat. Replacing the same amount of calories of alcoholic beverages with sugar sweetened beverages was equally associated with liver fat, whereas replacement with milk was associated with less liver fat. Lastly, we observed that objectively measured sedentary time was associated with more total body fat, visceral fat and liver fat. Replacing 30 minutes of sedentary time per day with moderate to vigorous physical activity, but not light physical activity was associated with less total body fat, visceral fat and liver fat. These associations with visceral fat and liver fat disappeared after additional adjustment for total body fat, indicating that there is no extra effect on visceral fat and liver fat beyond effects via total body fat.Results described in this thesis hint towards the importance of considering diet as a whole, instead of separate components, which is in line with the current dietary guidelines. Sedentary behaviour should be replaced with moderate to vigorous physical activity rather than light physical activity. Alcohol should not be replaced with sugar sweetened beverages, but rather with milk, coffee or tea. Show less
Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
Cardiometabolic disease such as obesity, type 2 diabetes, and atherosclerosis, are a leading cause of morbidity and mortality in the Western world. Two important risk factors for the development of... Show moreCardiometabolic disease such as obesity, type 2 diabetes, and atherosclerosis, are a leading cause of morbidity and mortality in the Western world. Two important risk factors for the development of cardiometabolic disease are hyperlipidemia and inflammation. Recently, evidence strongly indicates a role for the gut microbiota in the development of cardiometabolic disease. Therapeutic approaches are therefore aimed at modifying the gut microbiota composition and function to beneficially affect the development of cardiometabolic disease and its underlying risk factors. A potential candidate to modify gut microbiota composition are indigestible carbohydrates, or prebiotics. In this thesis, we aimed to understand the interplay between various indigestible carbohydrates, gut microbiota composition and function, and the development of obesity, type 2 diabetes, and atherosclerosis. Together, the studies described in this thesis increased our knowledge on the potential of various indigestible carbohydrates in the modulation of the gut microbiota to affect the development of cardiometabolic disease, suggesting a promising strategy to further pursue with some caution. Show less
In this thesis, the importance of visceral obesity in the relation of obesity with cardiometabolic risk factors (chapter 2) was confirmed and it was shown that in individuals free of known... Show moreIn this thesis, the importance of visceral obesity in the relation of obesity with cardiometabolic risk factors (chapter 2) was confirmed and it was shown that in individuals free of known cardiovascular disease clustering of cardiometabolic risk factors is associated with changes in electrocardiographic parameters indicative of subclinical cardiovascular disease (chapter 3). The findings from chapter 3 also point to the importance of the prevention of these metabolic syndrome components, not only in obese, but also in non-obese individuals. Furthermore, both overall and abdominal adiposity were found to be associated with these deleterious changes in electrocardiographic parameters (chapter 4). Borderline Q-waves were associated with a negative cardiovascular risk profile and increased pulse wave velocity and intima-media thickness (chapter 5). Chapter 6 shows that several cardiovascular risk factors were associated with a wider spatial QRS-T angle, which reflects ventricular electrophysiological heterogeneity. Both carotid intima-media thickness, as measure of subclinical atherosclerosis, and pulse wave velocity, as measure of arterial stiffness, were associated with a wider spatial QRS-T angle. In chapter 7, improvement of electrocardiographic detection of left ventricular hypertrophy with conventional electrocardiographic criteria by taking into account body mass index and the spatial QRS-T angle is shown. Show less
Obesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a... Show moreObesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a combination of known and unknown risk factors. Since effective long-term treatment strategies are currently lacking, the search for additional risk factors and development of targeted treatment strategies to combat these (cardio)metabolic diseases is warranted. An attractive approach seems to be activation of energy-combusting brown adipose tissue (BAT), which can result in increased energy expenditure and improvement in glucose and lipid metabolism. In this thesis, we aimed to address two key objectives: 1) unravelling the underlying mechanisms that could explain the increased predisposition for metabolic disease in the South Asian population, and 2) identifying novel pharmacological strategies that activate BAT and increase energy expenditure in risk populations, including South Asians and individuals with overweight and prediabetes. The studies described in this thesis have highlighted some novel factors, such as endocannabinoids and angiopoitein-like-protein-4, that might in part explain to unbeneficial metabolic phenotype of South Asians. In addition, novel potential therapeutic strategies were identified to combat metabolic disease, such as treatment with a β3-adrenergic receptor agonist and a dipeptidyl-peptidase-4 inhibitor. Show less
