Metabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an... Show moreMetabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an irreversible state of diabetes or cardiovascular disease. Much research has been done on the role of insulin signaling in metabolic disease, as well as the resultant disturbed lipid homeostasis present in cardiovascular disease and atherosclerosis. Here we add to existing work by developing new tools and sketching out the pathology of dysregulated adipose insulin signaling. We discuss the mechanism of lipodystrophy by using adipocytes differentiated from patient-derived iPSCs. These cells mimic the clinical phenotype and hint at mechanism that reduced patients’ adipose tissue mass. In mice we find that if we knock out the adipose insulin receptor, there is disrupted adipose and liver metabolism. There is a protection from diet-induced obesity, but a dramatically reduced lifespan. We also establish a relationship between obesity and inflammation by transcriptomically assessing obese human adipocytes. We find that an immune factor is responsible for lipid droplet formation and content. Lastly, we develop a new differentiation and purification strategy for iPSC-derived hepatocytes, which we employ to in vitro model a SNP that protects against cardiovascular disease. Show less
Cardiovascular disease is the leading cause of death in the western world. Frequent or chronic reductions in heart rate variability (HRV) are a powerful predictor of cardiovascular disease.... Show moreCardiovascular disease is the leading cause of death in the western world. Frequent or chronic reductions in heart rate variability (HRV) are a powerful predictor of cardiovascular disease. Psychological stress has been suggested to be an important factor in the development of reduced HRV. Recently, Verkuil et al. (2016) introduced a laboratory-based method to measure additional HRV reduction in everyday life, and reductions in HRV related to psychological stress. In the current paper, we discuss alternative methods to detect additional HRV reductions, in real life data sets without the necessity of laboratory-based calibration, and even in existing data sets. All of these methods use a subset of 24 h' worth of HRV and movement data to do so: either the first 10 min of every hour, the full 24 h, a combination of 10 min from three consecutive hours, or a classification of level of movement. We also present a method to visualize HRV and movement data to be able to detect episodes of reduced additional HRV optically. The method that used the full 24 h' worth of data detected the largest percentage of episodes of reduced additional HRV that actually match with self-reported stress levels, making this method the most promising. Show less
Manabe, O.; Kikuchi, T.; Scholte, A.J.H.A.; Mahdiui, M. el; Nishii, R.; Zhang, M.R.; ... ; Yoshinaga, K. 2018
Cardiovascular disease (CVD) is the leading cause of death in women in the Western world. In this thesis, several studies are presented examining the association between recurrent miscarriage and... Show moreCardiovascular disease (CVD) is the leading cause of death in women in the Western world. In this thesis, several studies are presented examining the association between recurrent miscarriage and cardiovascular disease. Main aim of this thesis was to assess whether miscarriages are independently associated with an increased risk of cardiovascular disease later in life. And, if this was true, to identify cardiovascular risk factors and predict long term cardiovascular disease risk in women with a history of recurrent miscarriage. We found an increased risk of ischemic heart disease in women with a history of two (multivariate analysis HR 1.82) and three or more miscarriages (HR 3.18), irrespective whether consecutive or not (chapter 2). Women with a history of recurrent miscarriage have significantly higher 10- and 30-year cardiovascular risk scores compared to women with a history of no miscarriage. These results indicate an opportunity for the early identification of women prone to cardiovascular disease later in life. Women with a history of two or more miscarriages must be made aware of their increased cardiovascular risk and appropriate risk factor modifications will have to be offered, for example life style advises; weight management and smoking control. Show less
Atherosclerotic changes of the carotid artery are associated with elevated cardiovascular risk. Non-invasive imaging studies of the artery can provide information on the presence or absence of... Show moreAtherosclerotic changes of the carotid artery are associated with elevated cardiovascular risk. Non-invasive imaging studies of the artery can provide information on the presence or absence of abnormalities. Although the techniques are extensively used in clinical research their implementation in common practice is not widespread. In this thesis the potential benefits and challenges of carotid imaging in clinical practice are studied. Ultrasound and magnetic resonance imaging are the two modalities of interest. The findings suggest that ultrasound can be performed by the clinician in a routine outpatient setting. Clinicians are able to detect atherosclerotic plaques but not intima-media thickness. Plaques are highly prevalent in asymptomatic primary prevention patients. Magnetic resonance imaging is a new highly reproducible modality but requires further clinical validation. Its utility in individual patient risk assessment is unclear and ultrasound validity cannot be extrapolated to magnetic resonance. The use of a combination of the two imaging modalities may allow for estimation of the lamina adventitia in vivo. Finally, interpretation of the imaging parameters must be done in conjunction with all cardiovascular risk factors and treatment decision should not be based on imaging results alone. Show less
Cardiovascular syndromes are the major cause of death in Western societies. The main underlying pathology is atherosclerosis, a chronic disease affecting the arteries. During atherosclerosis... Show moreCardiovascular syndromes are the major cause of death in Western societies. The main underlying pathology is atherosclerosis, a chronic disease affecting the arteries. During atherosclerosis progression, LDL, or “bad” cholesterol, accumulates in the arterial wall, resulting in the formation of a lipid-rich atherosclerotic plaque. This event activates the immune system, which increases plaque inflammation. Mast cells are components of the immune system known for their role in allergy. However, it has been established that mast cells are also important in atherosclerosis. In this PhD dissertation, we explored the interaction of mast cells with other immune cells. We examined the interrelation between mast cells and T-lymphocytes and discovered that mast cells can function as antigen presenting cells in atherosclerosis and, enhance the development of an atherosclerotic plaque via a direct interaction. Nonetheless, mast cells can also act on the Natural Killer T-cells, resulting in a protective function against atherosclerosis. Importantly, we used a relatively novel technical approach to explore the characteristics of mast cells inside human atherosclerotic plaques. We found that mast cells are highly activated and thus possibly promote disease progression. In conclusion, mast cells possess both protective and harmful effects, acting as regulators of the immune response in atherosclerosis. Show less
Mast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the... Show moreMast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. Depending on the stimulus, mast cell activation may also launch prolonged synthesis and secretion of single bioactive molecules, such as cytokines and derivatives of arachidonic acid. The mast cell-derived mediators may impede the functions of different types of cells present in atherosclerotic lesions, and also compromise the structural and functional integrity of the intimal extracellular matrix. In the adventitial layer of atherosclerotic coronary arteries, mast cells locate next to peptidergic sensory nerve fibers, which, by releasing neuropeptides may activate mast cells to release vasoactive compounds capable of triggering local vasoconstriction. The concerted actions of arterial mast cells have the potential to contribute to the initiation and progression of atherosclerosis, and ultimately to destabilization and rupture of an advanced atherosclerotic plaque with ensuing atherothrombotic complications Show less
Cardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the... Show moreCardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the effects of modulating circadian rhythms on energy metabolism using animal models and by studying plasma metaoblites and lipids in humans. Using animal studies we observed that brown adipose tissue (BAT) is strongly regulated by the biological clock, possibly via circadian glucocorticoid rhythms, and attenuated BAT activity through prolonged light exposure increases adiposity. Research focusing on the rhythm in human BAT, and regulation thereof, is necessary to confirm the translational value of our findings. We also observed that mistimed light exposure enhances atherosclerosis development, which may provide a mechanistic link between the known association between shift work and CVD. We anticipate that living according to the natural circadian rhythms presumably contributes to cardiometabolic health. Since disturbances in day-night rhythms are inevitable in modern society, in the future we may advise individuals at risk for development of CVD refrain from shift work and short sleep duration. In addition, data in this thesis may be useful to design strategies to avoid the disadvantageous metabolic effects of shift work. Show less
Bonten, T.N.; Mutsert, R. de; Rosendaal, F.R.; Jukema, J.W.; Bom, J.G. van der; Jongh, R.T. de; Heijer, M. den 2017
