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
Berg, I.J.; Semb, A.G.; Heijde, D. van der; Kvien, T.K.; Hisdal, J.; Olsen, I.C.; ... ; Provan, S.A. 2014
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
Yakala, G.K.; Wielinga, P.Y.; Suarez, M.; Bunschoten, A.; Golde, J.M. van; Arola, L.; ... ; Heeringa, P. 2013
