Atherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall,... Show moreAtherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall, resulting in plaque formation. It is well-known that atherosclerosis prevalence and manifestation vary by sex. However, sexual dimorphism in the immune landscape of atherosclerotic plaques has up to date not been studied at high-resolution. In this study, we investigated sex-specific differences in atherosclerosis development and the immunological landscape of aortas at single-cell level in aged Ldlr-/- mice.We compared plaque morphology between aged male and female chow diet-fed Ldlr-/- mice (22 months old) with histological analysis. Using single-cell RNA-sequencing and flow cytometry on CD45+ immune cells from aortas of aged Ldlr-/- mice, we explored the immune landscape in the atherosclerotic environment in males and females.We show that plaque volume is comparable in aged male and female mice, and that plaques in aged female mice contain more collagen and cholesterol crystals, but less necrotic core and macrophage content compared to males. We reveal increased immune cell infiltration in female aortas and found that expression of pro-atherogenic markers and inflammatory signaling pathways was enriched in plaque immune cells of female mice. Particularly, female aortas show enhanced activation of B cells (Egr1, Cd83, Cd180), including age-associated B cells, in addition to an increased M1/M2 macrophage ratio, where Il1b+ M1-like macrophages display a more pro-inflammatory phenotype (Nlrp3, Cxcl2, Mmp9) compared to males. In contrast, increased numbers of age-associated Gzmk+CD8+ T cells, dendritic cells, and Trem2+ macrophages were observed in male aortas.Altogether, our findings highlight that sex is a variable that contributes to immunological differences in the atherosclerotic plaque environment in mice and provide valuable insights for further preclinical studies into the impact of sex on the pathophysiology of atherosclerosis. Show less
Rakers, M.; Hattem, N. van; Simic, I.; Chavannes, N.; Peet, P. van; Bonten, T.; ... ; Os, H. van 2024
Background While remote patient management (RPM) has the potential to assist in achieving treatment targets for cardiovascular risk factors in primary care, its effectiveness may vary among... Show moreBackground While remote patient management (RPM) has the potential to assist in achieving treatment targets for cardiovascular risk factors in primary care, its effectiveness may vary among different patient subgroups. Panel management, which involves proactive care for specific patient risk groups, could offer a promising approach to tailor RPM to these groups. This study aims to (i) assess the perception of healthcare professionals and other stakeholders regarding the adoption and (ii) identify the barriers and facilitators for successfully implementing such a panel management approach. Methods In total, nineteen semi-structured interviews and two focus groups were conducted in the Netherlands. Three authors reviewed the audited transcripts. The Consolidated Framework for Implementation Strategies (CFIR) domains were used for the thematic analysis. Results A total of 24 participants (GPs, nurses, health insurers, project managers, and IT consultants) participated. Overall, a panel management approach to RPM in primary care was considered valuable by various stakeholders. Implementation barriers encompassed concerns about missing necessary risk factors for patient stratification, additional clinical and technical tasks for nurses, and reimbursement agreements. Facilitators included tailoring consultation frequency and early detection of at-risk patients, an implementation manager accountable for supervising project procedures and establishing agreements on assessing implementation metrics, and ambassador roles. Conclusion Panel management could enhance proactive care and accurately identify which patients could benefit most from RPM to mitigate CVD risk. For successful implementation, we recommend having clear agreements on technical support, financial infrastructure and the criteria for measuring evaluation outcomes. Show less
There is an increasing number of adults who suffer from cardiovascular diseases (CVD). These patients would benefit from a healthy lifestyle, as this improves the prognosis of CVD. However, even... Show moreThere is an increasing number of adults who suffer from cardiovascular diseases (CVD). These patients would benefit from a healthy lifestyle, as this improves the prognosis of CVD. However, even though improving one’s health and lifestyle is the focus of cardiac rehabilitation, CVD patients need support to also maintain a healthy lifestyle after their rehabilitation has ended. Even though the support of a healthcare professional seems to be an important factor in successful lifestyle change, there are barriers that hinder professionals from providing lifestyle support, such as a lack of time or expertise. Since the involvement of healthcare professionals is also not always possible or desirable, it is important to further investigate possibilities to provide patients with a self-help eHealth intervention. In such self-help eHealth interventions, feedback is automatically provided, making the interference of a healthcare professional no longer needed. However, self-help eHealth interventions can suffer from a low uptake and a low level of adherence. This PhD dissertation therefore focuses on (1) mapping out the needs and wishes of both healthcare professionals and CVD patients with regard to (human-supported and self-help) eHealth lifestyle interventions, and (2) investigating if and how self-help eHealth lifestyle interventions could be optimised. Show less
Two types of financial incentives can help improve healthy lifestyles: carrots (a reward where one can gain something) and sticks (a deposit contract where one can lose something). In a deposit... Show moreTwo types of financial incentives can help improve healthy lifestyles: carrots (a reward where one can gain something) and sticks (a deposit contract where one can lose something). In a deposit contract, participants deposit own money and can lose or earn it back depending on lifestyle changes. We studied the potential of deposit contracts to stimulate a healthy lifestyle.A smartphone app was developed together with the Swiss university ETH Zurich to conduct experimental research into the effects of deposit contracts. In addition, we collaborated with the American company WayBetter to observe the effects of commercially available deposit contracts. Finally, the opinion of people with cardiovascular disease and healthcare professionals regarding financial incentives and deposit contracts for lifestyle change was investigated.The results show that deposit contracts can have strong effects on exercise behavior (daily step counts) in the short term. The results also show that voluntary participation in deposit contracts is limited, but can be increased by doubling the amount deposited and by allowing participants to determine the amount themselves. Finally, healthcare providers think it is a good idea to use financial incentives, but people with cardiovascular disease themselves are skeptical about the use of deposit contracts. Show less
Elieh-Ali-Komi, D.; Bot, I.; Rodríguez-González, M.; Maurer, M. 2024
Mast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play a role in the... Show moreMast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play a role in the pathophysiology of non-allergic disorders including atherosclerosis. The involvement of MCs in the pathology of atherosclerosis is supported by their accumulation in atherosclerotic plaques upon their progression and the association of intraplaque MC numbers with acute cardiovascular events. MCs that accumulate within the atherosclerotic plaque release a cocktail of mediators through which they contribute to neovascularization, plaque progression, instability, erosion, rupture, and thrombosis. At a molecular level, MC-released proteases, especially cathepsin G, degrade low-density lipoproteins (LDL) and mediate LDL fusion and binding of LDL to proteoglycans (PGs). Through a complicated network of chemokines including CXCL1, MCs promote the recruitment of among others CXCR2+ neutrophils, therefore, aggravating the inflammation of the plaque environment. Additionally, MCs produce extracellular traps which worsen inflammation and contribute to atherothrombosis. Altogether, evidence suggests that MCs actively, via several underlying mechanisms, contribute to atherosclerotic plaque destabilization and acute cardiovascular syndromes, thus, making the study of interventions to modulate MC activation an interesting target for cardiovascular medicine. Show less
Cardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol... Show moreCardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol and lipid accumulation. Despite available effective cholesterol lowering medication, considerable risk for recurrent vascular events remains. This residual risk is at least in part explained by high blood lipid levels. The research described in this thesis revealed novel therapeutic strategies that improve lipid metabolism and reduce atherosclerosis development in mice. Inhibition of the endocannabinoid system was found to be an effective strategy, as well as concomitant activation of two incretin hormone receptors, namely those for GIP and GLP1. For combined GIP/GLP1 receptor agonism we additionally showed strongly attenuated hepatic steatosis. We were also able to identify additional targets to attenuate hyperlipidemia by studying the mechanisms underlying the strong day-night rhythm of brown adipose tissue, which is a lipid combusting tissue. In this thesis, I also stress the importance of the choice in animal model when studying lipid-modifying interventions, and describe the development of the software tool RandoMice which can be used to improve the quality of preclinical studies by creating well-balanced experimental groups. Show less
Zonneveld, M.H.; Trompet, S.; Jukema, J.W.; Noordam, R. 2023
Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring... Show moreProspective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e−7) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia. Show less
Eenige, R. van; Ying, Z.X.; Tramper, N.; Wiebing, V.; Siraj, Z.; Boer, J.F. de; ... ; Kooijman, S. 2023
Background and aims: Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in... Show moreBackground and aims: Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in terms of glycemic control and lowering body weight in individuals with obesity and with or without type 2 diabetes mellitus. As both GIPR and GLP1R signaling have also been implicated in improving inflammatory responses and lipid handling, two crucial players in atherosclerosis development, here we aimed to investigate the effects of combined GIPR/GLP1R agonism in APOE*3-Leiden.CETP mice, a well-established mouse model for human-like lipoprotein metabolism and atherosclerosis development. Methods: Female APOE*3-Leiden.CETP mice were fed a Western-type diet (containing 16% fat and 0.15% cholesterol) to induce dyslipidemia, and received subcutaneous injections with either vehicle, a GIPR agonist (GIPFA-085), a GLP1R agonist (GLP-140) or both agonists. In the aortic root area, atherosclerosis development was assessed. Results: Combined GIPR/GLP1R agonism attenuated the development of severe atherosclerotic lesions, while single treatments only showed non-significant improvements. Mechanistically, combined GIPR/GLP1R agonism decreased markers of systemic low-grade inflammation. In addition, combined GIPR/GLP1R agonism markedly lowered plasma triglyceride (TG) levels as explained by reduced hepatic very-low-density lipoprotein (VLDL)-TG production as well as increased TG-derived fatty acid uptake by brown and white adipose tissue which was coupled to enhanced hepatic uptake of core VLDL remnants. Conclusions: Combined GIPR/GLP1R agonism attenuates atherosclerosis severity by diminishing inflammation and increasing VLDL turnover. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to lower cardiometabolic risk in humans. Show less
The prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of... Show moreThe prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of the thesis focused on anti-oxidants, which are scavengers that protect against oxidative damage. We studied the association between several lifestyle factors, diet, physical activity, sleep, alcohol intake and smoking, and antioxidant levels both in blood and urine. Subsequently, we investigated whether a higher concentration of antioxidants leads to a decrease in ischaemic stroke occurrence. Next, we aimed to study a possible cause of oxidative damage and its effect on cardiovascular disease. Mitochondrial dysfunction is one of the mechanisms that may underly this effect. Mitochondria are an important source of Reactive Oxygen Species (ROS), as an inevitable byproduct of their essential role in energy production. A disbalance in ROS production and scavenging might result in oxidative damage. Thus, we investigated the causal association between mitochondrial dysfunction and stroke using the Mendelian Randomization method. Finally, we studied how socio-demographic traits could modify the causal association between CVD risk factors and coronary artery disease. Show less
Cardiovascular disease is the leading cause of death in the world. Therefore, there is an increasing need for accurate and efficient cardiovascular risk assessment to optimize cardiovascular... Show moreCardiovascular disease is the leading cause of death in the world. Therefore, there is an increasing need for accurate and efficient cardiovascular risk assessment to optimize cardiovascular treatment. The aorta plays a central role in the cardiovascular system, transporting blood to various organ systems while absorbing the pulsatile pressure of the cardiac output. Aortic stiffness is a marker of vascular aging and has shown to be an independent marker for cardiovascular risk. Additionally, enlarged aortic dimensions are linked to an increased risk of rupture. MRI is capable of providing accurate information on aortic morphology, stiffness and blood flow patterns.In this thesis we expanded the potential clinical utility of MRI-based measures of aortic morphology and function in the assessment of cardiovascular risk and further unravelled complex cardiovascular systemic interactions using MRI. We provided standardized methods and reference values for fundamental MRI-based measures of aortic morphology and function, explored new methods to make PWV more accessible, evaluated the prognostic value of MRI-based measures of aortic morphology and function and explored systemic interactions of cardiovascular function with obesity as well as the brain. These studies contribute to more accurate and accessible cardiovascular risk assessment, which eventually can lead to improved cardiovascular treatment. Show less
Background Socioeconomic status and ethnicity are not explicitly incorporated as risk factors in the four SCORE2 cardiovascular disease (CVD) risk models developed for country-wide implementation... Show moreBackground Socioeconomic status and ethnicity are not explicitly incorporated as risk factors in the four SCORE2 cardiovascular disease (CVD) risk models developed for country-wide implementation across Europe (low, moderate, high and very-high model). The aim of this study was to evaluate the performance of the four SCORE2 CVD risk prediction models in an ethnic and socioeconomic diverse population in the Netherlands.Methods The SCORE2 CVD risk models were externally validated in socioeconomic and ethnic (by country of origin) subgroups, from a population-based cohort in the Netherlands, with GP, hospital and registry data. In total 155,000 individuals, between 40 and 70 years old in the study period from 2007 to 2020 and without previous CVD or diabetes were included. Variables (age, sex, smoking status, blood pressure, cholesterol) and outcome first CVD event (stroke, myocardial infarction, CVD death) were consistent with SCORE2. Findings 6966 CVD events were observed, versus 5495 events predicted by the CVD low-risk model (intended for use in the Netherlands). Relative underprediction was similar in men and women (observed/predicted (OE-ratio), 1.3 and 1.2 in men and women, respectively). Underprediction was larger in low socioeconomic subgroups of the overall study population (OE-ratio 1.5 and 1.6 in men and women, respectively), and comparable in Dutch and the combined "other ethnicities" low socioeconomic subgroups. Underprediction in the Surinamese subgroup was largest (OE-ratio 1.9, in men and women), particularly in the low socioeconomic Surinamese subgroups (OE-ratio 2.5 and 2.1 in men and women). In the subgroups with underprediction in the low-risk model, the intermediate or high-risk SCORE2 models showed improved OE-ratios. Discrimination showed moderate performance in all subgroups and the four SCORE2 models, with C-statistics between 0.65 and 0.72, similar to the SCORE2 model development study.Interpretation The SCORE 2 CVD risk model for low-risk countries (as the Netherlands are) was found to underpredict CVD risk, particularly in low socioeconomic and Surinamese ethnic subgroups. Including socioeconomic status and ethnicity as predictors in CVD risk models and implementing CVD risk adjustment within countries is desirable for adequate CVD risk prediction and counselling. Show less
Cardiovascular disease (CVD) is a major cause of death worldwide. The underlying cause of most CVD is atherosclerosis. Atherosclerosis is characterized by progressive plaque build-up in the... Show moreCardiovascular disease (CVD) is a major cause of death worldwide. The underlying cause of most CVD is atherosclerosis. Atherosclerosis is characterized by progressive plaque build-up in the arterial wall.Noncoding RNAs (ncRNAs) are RNAs that are not translated into protein. This thesis focuses on two types: microRNAs and small nucleolar RNAs (snoRNAs). MicroRNAs inhibit the production of proteins and act on multiple proteins simultaneously. In CVD, many different proteins are involved. Changing expression of one microRNA can therefore have a major impact.Numerous snoRNAs have been associated with diseases, including CVD. The function of half of the human C/D box snoRNAs, however, is unknown.The first aim of this thesis is to investigate inhibition of microRNA-494-3p in advanced atherosclerosis. The second aim is to elucidate the function of SNORD113-6, a snoRNA that is involved in CVD.The thesis shows that inhibition of microRNA-494-3p halts plaque progression and increases stability of advanced plaques. This reduces the risk of e.g. a myocardial infarction.Furthermore, SNORD113-6 influences the function of fibroblasts, scar cells, and thus plays a role in maintaining function of our blood vessels.These insights may open up new therapeutic possibilities in future treatment of CVD. Show less
Objective: Prediction models for cardiovascular disease (CVD) mortality come from high-income countries, comprising laboratory measurements, not suitable for resource-limited countries. This study... Show moreObjective: Prediction models for cardiovascular disease (CVD) mortality come from high-income countries, comprising laboratory measurements, not suitable for resource-limited countries. This study aims to develop and validate a non-laboratory model to predict CVD mortality in a middle-income setting. Study design and setting: We used data of population aged 40-80 years from three cohort studies: Tehran Lipid and Glucose Study (n = 5160), Isfahan Cohort Study (n = 4350), and Golestan Cohort Study (n = 45,500). Using Cox proportional hazard models, we developed prediction models for men and women, separately. Cross-validation and bootstrapping procedures were applied. The models' discrimination and calibration were assessed by concordance statistic (C-index) and calibration plot, respectively. We calculated the models' sensitivity, specificity and net benefit fraction in a threshold probability of 5%. Results: The 10-year CVD mortality risks were 5.1% (95%CI: 4.8-5.5) in men and 3.1% (95%CI: 2.9%-3.3%) in women. The optimism-corrected performance of the model was c = 0.774 in men and c = 0.798 in women. The models showed good calibration in both sexes, with a predicted-to-observed ratio of 1.07 in men and 1.09 in women. The sensitivity was 0.76 in men and 0.66 in women. The net benefit fraction was higher in men compared to women (0.46 vs. 0.35). Conclusion: A low-cost model can discriminate well between low-and high-risk individuals, and can be used for screening in low-middle income countries. (C)& nbsp;2021 Elsevier Inc. All rights reserved. Show less
Douna, H.; Mol, J. de; Amersfoort, J.; Schaftenaar, F.H.; Kiss, M.G.; Suur, B.E.; ... ; Foks, A.C. 2022
B and T cells are interconnected in the T follicular helper-germinal center B cell (TFH-GC B cell) axis, which is hyperactive during atherosclerosis development and loss of control along this axis... Show moreB and T cells are interconnected in the T follicular helper-germinal center B cell (TFH-GC B cell) axis, which is hyperactive during atherosclerosis development and loss of control along this axis results in exacerbated atherosclerosis. Inhibition of the TFH-GC B cell axis can be achieved by providing negative co-stimulation to TFH cells through the PD-1/PD-L1 pathway. Therefore, we investigated a novel therapeutic strategy using PD-L1-expressing B cells to inhibit atherosclerosis. We found that IFNγ-stimulated B cells significantly enhanced PD-L1 expression and limited TFH cell development. To determine whether IFNγ-B cells can reduce collar-induced atherosclerosis, apoE -/- mice fed a Western-type diet were treated with PBS, B cells or IFNγ-B cells for a total of 5 weeks following collar placement. IFNγ-B cells significantly increased PD-L1hi GC B cells and reduced plasmablasts. Interestingly, IFNγ-B cells-treated mice show increased atheroprotective Tregs and T cell-derived IL-10. In line with these findings, we observed a significant reduction in total lesion volume in carotid arteries of IFNγ-B cells-treated mice compared to PBS-treated mice and a similar trend was observed compared to B cell-treated mice. In conclusion, our data show that IFNγ-stimulated B cells strongly upregulate PD-L1, inhibit TFH cell responses and protect against atherosclerosis. Show less
Velden, J. van der; Asselbergs, F.W.; Bakkers, J.; Batkai, S.; Bertrand, L.; Bezzina, C.R.; ... ; Thum, T. 2022
Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of... Show moreCardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models cannot provide a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on a organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept. Show less
Slenders, L.; Landsmeer, L.P.L.; Cui, K.; Depuydt, M.A.C.; Verwer, M.; Mekke, J.; ... ; Laan, S.W. van den, Mokry, M. 2021
Genome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into... Show moreGenome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analysed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene-cell pairs.\nWe applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with single-cell RNA sequencing (scRNA-seq) data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease (CAD) loci demonstrated a prominent signal in plaque smooth muscle cells (SMCs) (SKI, KANK2, and SORT1) P-adj. = 0.0012, and endothelial cells (ECs) (SLC44A1, ATP2B1) P-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels.\nWe discovered novel and known gene-cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with CAD reveal prominent association levels in mainly plaque SMC and EC populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits. Show less
This thesis investigates the effectiveness and safety of treatments in patients with cardiovascular and kidney disease. Routinely collected healthcare data provide an immense opportunity to... Show moreThis thesis investigates the effectiveness and safety of treatments in patients with cardiovascular and kidney disease. Routinely collected healthcare data provide an immense opportunity to investigate such questions in populations underrepresented in clinical trials, such as patients with advanced chronic kidney disease (CKD).The first part of this thesis deals with how to appropriately use routinely collected data to answer causal questions. It illustrates what study designs eliminate commonly occurring biases, namely immortal time and prevalent user bias, and how to use propensity scores to correctly adjust for confounding in the setting of time-fixed and time-varying treatments.The second part investigates the effectiveness and safety of various treatments. For instance, the effectiveness of beta-blockers in patients with heart failure and advanced CKD is investigated. Renin-angiotensin system inhibitors (RASi) are an especially widely used medication class in CKD patients. The relationship between the magnitude of renal function decline - which is commonly observed after initiation of these drugs - with mortality and cardiorenal outcomes is investigated. In addition, comparative effectiveness study of RASi and calcium channel blockers among patients with advanced CKD is performed. In the last two chapters, a target trial is explicitly emulated to investigate the effect of stopping or continuing RASi and the optimal timing to start dialysis in patients with advanced chronic kidney disease. Show less
Objective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at... Show moreObjective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at external validation. Study Design and Setting: We evaluated risk of bias (ROB) on 102 CPMs from the Tufts CPM Registry, comparing PROBAST to a short form consisting of six PROBAST items anticipated to best identify high ROB. We then applied the short form to all CPMs in the Registry with at least 1 validation (n = 556) and assessed the change in discrimination (dAUC) in external validation cohorts (n = 1,147). Results: PROBAST classified 98/102 CPMS as high ROB. The short form identified 96 of these 98 as high ROB (98% sensitivity), with perfect specificity. In the full CPM registry, 527 of 556 CPMs (95%) were classified as high ROB, 20 (3.6%) low ROB, and 9 (1.6%) unclear ROB. Only one model with unclear ROB was reclassified to high ROB after full PROBAST assessment of all low and unclear ROB models. Median change in discrimination was significantly smaller in low ROB models (dAUC -0.9%, IQR -6.2-4.2%) compared to high ROB models (dAUC -11.7%, IQR -33.3-2.6%; P < 0.001). Conclusion: High ROB is pervasive among published CPMs. It is associated with poor discriminative performance at validation, supporting the application of PROBAST or a shorter version in CPM reviews. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http:// creativecommons.org/ licenses/ by- nc- nd/ 4.0/ ) Show less
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have... Show moreCardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options. Show less
Background and aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles... Show moreBackground and aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles Methods: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two & times; two design with the group with genetically-influenced high TG and LDL-C as a reference. Results: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 & times; 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. Conclusions: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction. Show less
