Artificial intelligence (AI) has transformed key aspects of human life. Machine learning (ML), which is a subset of AI wherein machines autonomously acquire information by extracting patterns from... Show moreArtificial intelligence (AI) has transformed key aspects of human life. Machine learning (ML), which is a subset of AI wherein machines autonomously acquire information by extracting patterns from large databases, has been increasingly used within the medical community, and specifically within the domain of cardiovascular diseases. In this review, we present a brief overview of ML methodologies that are used for the construction of inferential and predictive data-driven models. We highlight several domains of ML application such as echocardiography, electrocardiography, and recently developed non-invasive imaging modalities such as coronary artery calcium scoring and coronary computed tomography angiography. We conclude by reviewing the limitations associated with contemporary application of ML algorithms within the cardiovascular disease field. Show less
This thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis... Show moreThis thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis on statin-induced HDL-C response by the Genomic Investigation of consortium, which identified CETP as a loci of interest, and two-sample Mendelian randomization studies utilizing summary level data from the GIST and other GWAS consortia on fasted blood lipids and type 2 diabetes. We additionally examine the issue of survival bias in Mendelian randomization studies. Finally, we show that intra-individual lipid variability associates with worse neurocognitive outcomes in older individuals at high risk for vascular disease, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. Show less
Aims There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention... Show moreAims There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29 39% of individuals aged >= 40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44 51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.Conclusion Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. Show less
Atherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the... Show moreAtherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the vessel wall. Over time, this accumulation of lipids and immune cells induce morphological abnormalities in the vessel wall which cause the vessel lumen to narrow. This narrowing of the lumen (stenosis) causes ischemia in the downstream tissue. Prolonged ischemia causes myocardial ischemia and/or stroke. The research described in my thesis examines a well-recognized risk factor of atherosclerosis, being dyslipidemia, from an entirely new perspective. More specifically, it describes how dyslipidemia affects intrinsic metabolic processes in T cells, the conductors of the immune response characterizing atherosclerosis, and how this affects their function. My research has contributed to knowledge on the pathophysiology of atherosclerosis and might one day pave the way for the development of novel therapeutic approaches to treat cardiovascular disease. Show less
Meeuwsen, J.A.L.; Vries, J.J. de; Duijvenvoorde, A. van; Velden, S. van der; Laan, S.W. van der; Koeverden, I.D. van; ... ; Jager, S.C.A. de 2019
future AbstractMouse studies have established distinct monocyte subtypes that participate in the process of atherosclerotic lesion formation. The pro-inflammatory Ly6Chigh monocyte subtype actively... Show morefuture AbstractMouse studies have established distinct monocyte subtypes that participate in the process of atherosclerotic lesion formation. The pro-inflammatory Ly6Chigh monocyte subtype actively contributes to murineplaque progression and destabilization. Also in humans, different peripheral monocyte subtypes have been identified, of which the CD14+CD16− classical monocyte is suggested to display similar pro-atherosclerotic properties as the murine Ly6Chigh subtype. We aimed to investigate if circulating CD14+CD16− classical monocytes associate with characteristics of a vulnerable carotid atherosclerotic plaque and if they associate with the risk of secondary adverse manifestations of atherosclerotic disease.We enrolled 175 carotid endarterectomy patients of the Athero-Express biobank in our study. Just prior to surgical procedure, blood was collected and peripheral blood mononuclear cells were isolated. Characterization of monocyte subsets was performed by flow cytometry. Plaque characteristics were semi-quantitatively scored for the presence of fat, collagen, intraplaque hemorrhage and calcification. Vessel density, smooth muscle cells and macrophages were assessed quantitatively on a continuous scale. All features of a vulnerable plaque phenotype, including low amounts of collagen and smooth muscle cells, and increased fat content, vessel density, intraplaque hemorrhage and plaque macrophages were not significantly associated with differential levels of peripheral classical CD14+CD16− monocytes or other monocyte subsets. Using Cox regression models to evaluate the prognostic value of circulating monocyte subtypes, we found that total counts of peripheral monocytes, as well as CD14+CD16− classical and other monocyte subtypes were not associated with the risk of secondary cardiovascular events during 3 years follow-up.Circulating classical CD14+CD16− monocytes do not associate with specific vulnerable plaque characteristics. In addition, they do not predict secondary adverse manifestations. This suggests that in patients with established carotid artery disease, the circulating monocytes do not reflect plaque characteristics and have no value in identifying patients at risk for future cardiovascular events. Show less
Purpose:Cardiac rehabilitation in older patients after hospitalization because of cardiovascular disease is recommended. However, many older patients do not receive cardiac rehabilitation in daily... Show morePurpose:Cardiac rehabilitation in older patients after hospitalization because of cardiovascular disease is recommended. However, many older patients do not receive cardiac rehabilitation in daily practice, due to lack of referral and poor adherence. This can be related to impaired clinical and functional status of these patients, who are more likely to present with frailty, frequent comorbidities, and disability. Geriatric rehabilitation might be a possible solution to reduce barriers to cardiac rehabilitation attendance. We developed and implemented an inpatient geriatric rehabilitation programme that was provided immediately after discharge from the hospital, for older patients with a significant functional decline during hospital admission because of cardiovascular disease: 'the GR-cardio programme'. The primary aim of the present study is to investigate feasibility of the GR-cardio programme.Methods:This is a retrospective real-life feasibility study describing a consecutive series of older patients receiving the GR-cardio programme, with no control group. All patients had been hospitalized because of cardiovascular disease. Data on patient characteristics, functional status, health-related quality of life (HRQoL), readmissions, and mortality were collected from the patients file on admission, at discharge and 6 months after discharge from the GR-cardio programme. Feasibility of the programme was evaluated using the following outcomes: recruitment, resulting sample characteristics, safety, and preliminary evaluation of patients' responses to the GR-cardio programme.Results:In total, 58 patients [mean age 78.8 (± 9.8) years; 43% male] were included in the study. On admission, functional status and HRQoL were severely impaired but showed clinically relevant improvements. During the programme, three patients died. Eighty-three percent of all patients were discharged back home after completing the rehabilitation programme with a mean length of 38 days. Mortality rate during follow-up was the highest in patients with heart failure (32%).Conclusions:This study indicates that geriatric rehabilitation for patients with cardiovascular disease is feasible. Furthermore, our results show that the GR-cardio programme can probably offer substantial benefits for patients in terms of improving functional status and HRQoL. Show less
Limiting the pro-inflammatory immune response is critical for the treatment of atherosclerosis. Regulatory B cells (Bregs) can modulate the immune response through interleukin-10 (IL-10). Current... Show moreLimiting the pro-inflammatory immune response is critical for the treatment of atherosclerosis. Regulatory B cells (Bregs) can modulate the immune response through interleukin-10 (IL-10). Current data regarding Bregs and atherosclerosis is scarce and conflicting.\n B cells on atherosclerosis.\n B cells on atherosclerosis.\n B cells in atherosclerosis. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. 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