The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2... Show more The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2 diabetes have a 2- to 3-fold increased risk of cardiovascular disease. We investigated whether insulin resistance and hyperglycemia are associated with atherosclerosis and incident cardiovascular disease before the onset of type 2 diabetes. Obesity can be considered as a common cause of both insulin resistance and atherosclerosis. Therefore, we investigated to what extent associations between insulin resistance, hyperglycemia and atherosclerosis were explained by body fat. We further aimed to study the specific role of visceral fat in the development of insulin resistance and atherosclerosis, and directly assessed abdominal subcutaneous and visceral adipose tissue depots. Show less
In this thesis we observe that prescription rates of lipid-lowering drugs and antithrombotic medication in secondary prevention in old age are low. According to focus-group discussions with general... Show moreIn this thesis we observe that prescription rates of lipid-lowering drugs and antithrombotic medication in secondary prevention in old age are low. According to focus-group discussions with general practitioners highly individualized care with the ultimate aim to improve quality of life, might largely explain these low prescription rates; however, improvements might be expected from structured follow up, and tailored, age-specific guidelines, reflecting the heterogeneity of clinical practice. In very old age we observed that the severity of the cardiovascular disease history is associated with unfavourable prognosis, not only with regard to (recurrent) cardiovascular disease/mortality, but also with regard to future disability and cognitive decline. Of four newer cardiovascular risk markers N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of cardiovascular events/mortality in secondary cardiovascular prevention in very old age. NT-proBNP was also associated with cognitive and functional decline. Finally NT-proBNP predicted treatment effect of pravastatin. In order to improve patient care in older age, the following actions are recommended: vigorous ICPC coding and pro-active follow-up of all older patients with a history of cardiovascular disease. Finally, optimisation of secondary cardiovascular prevention is advised by individualised risk prediction and consciously weighing all pros and cons of preventive treatment. Show less
During this research project we studied circulating cells in the blood of people with cardiovascular disease, we investigated if these cells could be used as biomarkers for future cardiovascular... Show moreDuring this research project we studied circulating cells in the blood of people with cardiovascular disease, we investigated if these cells could be used as biomarkers for future cardiovascular incidents. We specifically looked at circulating immune cells such as monocytes, T cells and neutrophils. It was shown that both specific subsets of monocytes as well as neutrophils could be used to predict cardiovascular events in patients with cardiovascular disease. Surprisingly it was shown that different cell subsets were predictive for cardiovascular events in men and women. Investigating the difference between men and women further we show that the acute immune response in during cardiovascular disease is different between men and women. While the response in males was skewed towards a monocyte response, in women the acute response was skewed towards a T cell response. The research presented in this thesis shows that our knowledge of the gender specific immune response in cardiovascular disease is limited and further research is necessary. Show less
Atherosclerosis is a chronic inflammatory disease in which lipids and cells of the immune system accumulate in the vessel wall. Clinical complications, such as a myocardial infarction or stroke may... Show moreAtherosclerosis is a chronic inflammatory disease in which lipids and cells of the immune system accumulate in the vessel wall. Clinical complications, such as a myocardial infarction or stroke may occur when advanced atherosclerotic lesions become unstable and rupture. In this thesis, the influence of the psychological stress response and stress-related neuropeptides on vascular inflammation and atherosclerotic lesion development has been investigated. We demonstrated that acute stress results in activation of a potent type of immune cell in the vessel wall, the mast cell, leading to increased inflammation and atherosclerotic plaque destabilization. Furthermore, we have shown that (peri)vascular mast cell activation leads to neutrophil recruitment, thus aggravating the local inflammatory response. In addition, we demonstrated increased expression of neuropeptide Y in advanced atherosclerotic lesions and that overexpression of this peptide results in increased lesion development. These insights emphasize a contributing role for psychological stress to atherosclerotic lesion development and as a risk factor for acute cardiovascular syndromes and opens up new avenues for possible future anti-inflammatory therapies to reduce the risk of cardiovascular disease. Show less
In this thesis, senescence is measured in human populations according to its definition of an increase in the risks of dysfunction, disease, and death with chronological age. Part I of this thesis... Show moreIn this thesis, senescence is measured in human populations according to its definition of an increase in the risks of dysfunction, disease, and death with chronological age. Part I of this thesis investigates how a population__s senescence rate can be measured through the increase in mortality rate with age. Part II of this thesis investigates how senescence can be measured through the increase in morbidity - with a focus on cardiovascular disease - in a non-western population and thus be compared with the senescence process in western populations. Show less
With increasing age, incidence and prevalence of cardiovascular disease increase. Many physicians face the dilemma whether or not to start preventive treatment in old age. To help physicians decide... Show moreWith increasing age, incidence and prevalence of cardiovascular disease increase. Many physicians face the dilemma whether or not to start preventive treatment in old age. To help physicians decide whether to advise preventive medication to their older patients, prediction of those at highest or lowest (relative) risk using (preferably) inexpensive and easy to use cardiovascular risk factors is important. However, in old age there is a lack of good cardiovascular risk predictors. This thesis shows that the use of multiple blood pressure measurements expressed in the variability (in diastolic blood pressure) or trends in blood pressure can identify older persons with high cardiovascular risk. It also shows that in the oldest old, the absence or presence of heart failure does not influence the prognostic value of low systolic blood pressure regarding risk of death. The serological biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) is found to be an interesting candidate in cardiovascular risk prediction in old age, especially in secondary prevention. In the oldest old, an increase in NT-proBNP still reflects increased risk of (cardiovascular) death, independent of decreasing renal function and is associated with incident heart failure and atrial fibrillation. Show less
Kühnast, S.; Fiocco, M.; Hoorn, J.W.A. van der; Princen, H.M.G.; Jukema, J.W. 2015
Atherosclerosis is the main underlying pathology of cardiovascular disease, the largest single cause of death in industrialized countries, and current treatment is still largely insufficient. In... Show moreAtherosclerosis is the main underlying pathology of cardiovascular disease, the largest single cause of death in industrialized countries, and current treatment is still largely insufficient. In recent years it has become evident that immune responses contribute to atherosclerosis. Therefore, during my PhD studies I focused on developing a therapy to induce and expand anti-inflammatory immune cells to reduce ongoing immune responses and atherosclerosis. I used the approach of cellular therapy and examined the effect of several different anti-inflammatory immune cells. For example, I made use of mesenchymal stem cells, which have previously been used to improve cardiac repair after myocardial infarction and were found to have anti-inflammatory properties. Additionally, I used drugs, e.g. inhibitors of protein degradation, and biologics, e.g. components of heat-killed bacteria, to directly increase the amount of anti-inflammatory immune cells. An interesting side-effect of some treatments was that they additionally reduced cholesterol levels. In summary, I have shown in pre-clinical models that immune cell-based therapies are promising for the treatment of atherosclerosis. As atherosclerosis is determined by both high cholesterol levels and inflammation reducing immune responses will greatly contribute to a better treatment of cardiovascular patients in the (near) future. Show less
Aim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the... Show moreAim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the Genomic investigation of Statin Therapy (GIST) consortium are presented. We identified and validated two new GWAS loci to be associated with LDL-cholesterol response after statin treatment. In addition, we confirmed two previous identified loci. In chapter 5 we showed that we were not able to identify any loci associated with differential event reduction after statin therapy within the PROSPER study. The results presented in chapter 8 show that even at old age a genetic predisposition to high LDL-cholesterol is a risk factor for mortality. The results of this thesis show that currently the possibilities to personalize statin treatment based on genetic variants is limited. New research methods will hopefully give new opportunities to improve cardiovascular disease treatment and give more insight into the biological mechanisms of statin treatment. 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
Epigenetic mechanisms regulate cellular gene expression potential without changing the genetic code. Like the genetic sequence, epigenetic marks are faithfully transmitted during mitosis and are... Show moreEpigenetic mechanisms regulate cellular gene expression potential without changing the genetic code. Like the genetic sequence, epigenetic marks are faithfully transmitted during mitosis and are generally stable in differentiated cells, but in contrast with the static genome, the epigenome retains the capacity for dynamic changes in each individual cell. Epigenetic variation is therefore a topic of interest for research on ageing and its related common diseases. In this thesis we focus on DNA methylation, which is the most studied layer of epigenetic information,and is correlated to the other epigenetic layers. We used a combination of successive studies to investigate aspects of variation in DNA methylation, various sources generating such variation and its relation with risk for myocardial infarction (MI) at candidate loci for cardiovascular and metabolic diseases Show less
Current therapies for patients with atherosclerosis are targeted primarily on reducing blood cholesterol, but this fails to prevent a large number of cardiovascular events.95 In order to identify... Show moreCurrent therapies for patients with atherosclerosis are targeted primarily on reducing blood cholesterol, but this fails to prevent a large number of cardiovascular events.95 In order to identify new therapeutic strategies for treating atherosclerosis, it is important to study the interactions between the cells that make up the atherosclerotic lesion. This thesis describes the role of endothelial cells and macrophages during lesion formation, as well as the expression patterns of sterol sensors in vascular smooth muscle cells present in the lesion. These new insights contribute to our understanding of atherosclerosis open up new avenues of atherosclerosis research Show less
Atherosclerosis is a chronic inflammatory disease, consisting of the buildup of lipids in the vessel wall. Advanced lesions may become unstable and rupture, leading to major cardiovascular... Show moreAtherosclerosis is a chronic inflammatory disease, consisting of the buildup of lipids in the vessel wall. Advanced lesions may become unstable and rupture, leading to major cardiovascular complications such as myocardial infarction or stroke. In this thesis, the role of the innate immune system in atherosclerosis has been investigated. We have shown that inhibition of complement component C5a results in reduced atherosclerotic lesion formation as well as reduced lesion destabilization. Also, we have provided evidence that activation of mast cells surrounding the atherosclerotic lesion results in increased accumulation of the neutrophil, thus aggravating the local inflammatory response. Moreover, we have investigated the effect of microRNA inhibition of atherosclerosis. MicroRNAs are short non-coding RNA strands with the ability to modulate the expression of multiple genes. With a unique Reversed Target Prediction we have identified microRNAs that are predicted to affect multiple atherosclerosis-related genes. We inhibited one of these predicted microRNAs: microRNA-494, and investigated its role in vivo. Interestingly, we observed a striking reduction in atherosclerotic lesion formation, as well as an increase in lesion stability. Show less
Patients with end-stage renal disease have an approximate eight fold increased mortality rate due to cardiovascular causes as compared with individuals of equal age and sex without renal... Show morePatients with end-stage renal disease have an approximate eight fold increased mortality rate due to cardiovascular causes as compared with individuals of equal age and sex without renal dysfunction. Whereas traditional cardiovascular risk factors (such as smoking, hypertension and obesity) fail to completely explain this surplus in risk, nontraditional risk factors seem of pathophysiological importance. This thesis aimed at studying the impact of an increased inflammatory state and nonthyroidal illness as potential nontraditional cardiovascular risk factors in patients with end-stage renal disease. Show less
The studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell... Show moreThe studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell tumour (GCT) patients. We report a twofold increased prevalence of Metabolic Syndrome (MetS) in GCT patients who received chemotherapy compared to that in patients with stage 1 disease who did not receive chemotherapy, or to that in healthy controls. Thereafter, we describe disadvantageous metabolic changes and acute alterations in diastolic heart function in GCT patients treated with cisplatin-based chemotherapy. In the same group of patients we show that, during chemotherapy administrations, serum non-protein bound iron concentrations were inversely related to the latent iron-binding capacity and serum iron concentrations. This suggests that chemotherapy-associated iron overload may play a role in short and long-term chemotherapy induced toxicity in GCT patients. The study on bone metabolism shows an increased prevalence of vertebral fractures, independent of BMD and anticancer treatment, in newly diagnosed as well as long term survivors of testicular cancer. The last chapter reports on a significant decline in lumbar and femoral BMD in metastatic GCT patients one year after chemotherapeutic treatment. Show less
Calcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF)... Show moreCalcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about acute rejection. Therapeutic drug monitoring (TDM) may be advantageous when a CNI or MMF is withdrawn. The impact of late concentration-controlled CNI withdrawal with MMF on renal function, the incidence of acute rejection and markers of cardiovascular disease was evaluated in a randomised trial. In 158 stable renal transplant recipients on a CNI-based regimen with prednisone and MMF either the CNI or MMF was withdrawn. A total of 119 patients participated in the cardiovascular substudy. Late concentration-controlled CNI withdrawal resulted in improved renal function, especially in patients with an estimated glomerular filtration rate of less than 50 ml/min/1.73 m2, with a low acute rejection rate. The progression of left ventricular diastolic dysfunction was prevented by CNI elimination. CNI withdrawal decreased ambulatory blood pressures, but had no specific impact on carotid IMT. In conclusion, late CNI withdrawal with TDM of MMF may result in improved outcome by beneficial effects on renal function and cardiovascular risk, with a low risk of rejection in the majority of stable renal transplant recipients. Show less
The aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our... Show moreThe aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our findings indicate that people with more severe symptoms of depression and anxiety are at particular risk of progressive dyslipidemia and (abdominal) obesity. The higher rates of smoking and systemic inflammation among people with depression or anxiety partially accounted for their adverse metabolic profile. Dysregulations of the autonomic nervous system partly explained why users of tricyclic antidepressants displayed an increased risk of dyslipidemia and (abdominal) obesity as well, and also of hypertension. These important findings shed light on useful avenues for future research, and on preventive and therapeutic insights and directions. Show less
Obesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public... Show moreObesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public health. Excessive energy intake is an important cause of obesity since excess energy is primarily stored as fat. The stored fat is mobilized again during fasting in the form of fatty acids (FA). These FA are re-esterified in the liver in triglycerides (TG) that are secreted in VLDL particles to deliver FA to peripheral tissues where they can be used for energy. One of the current views of the cause of diseases related to obesity is the (mis)handling of TG derived FA. Therefore it is important to understand pathways involved in the uptake, distribution, oxidation and storage of TG. In this thesis we have evaluated the effect of different interventions on VLDL-TG metabolism to gain a better understanding of its complex regulation. For these studies we used APOE*3-Leiden (E3L) and E3L.CETP transgenic mice that have a human-like lipoprotein metabolism and respond to lipid-modifying drugs in a ways similar to humans. 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
Cardiovascular disease is an important problem in the western world and identification of individuals at risk of cardiovascular disease and identification of patients with cardiovascular disease... Show moreCardiovascular disease is an important problem in the western world and identification of individuals at risk of cardiovascular disease and identification of patients with cardiovascular disease who are at risk of complications is important in order to reduce morbidity and mortality. This thesis shows the potential of MRI for risk stratification in cardiovascular disease. MRI enables assessment of morphology and function of the aortic vessel wall, which is important since the thickness and stiffness of the aortic vessel wall are related with coronary artery disease and cardiovascular events. Furthermore, the potential of MRI for visualization of the coronary arteries and assessment of coronary artery flow is explored. Although, this technique is not yet routinely used, ongoing research may in the future make MRI a valuable technique for detection of coronary artery disease. In addition, it is demonstrated that MRI is an excellent technique for detection and quantification of valve regurgitation. MRI also allows for quantification of scar tissue and contractile reserve in patients with ischemic cardiomyopathy enabling assessment of viability, which is important for optimization of treatment and prognosis. Finally, it is demonstrated that infarct size and infarct tissue heterogeneity measured with MRI are important predictors for long-term survival. Show less
