A strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy... Show moreA strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy remained unknown. This thesis therefore studied the cardiovascular disease burden within this patient group. These results showed that the prevalence of atherosclerosis (i.e. cardiovascular disease burden), in contrast to abdominal aortopathy, is not increased within the thoracic aortopathy population. Show less
Smit, V.; Mol, J. de; Bernabé Kleijn, M.N.A.B.; Depuydt, M.A.C.; Winther, M.P.J. de, Bot, I.; Kuiper, J.; Foks, A.C. 2024
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
Tissue resident memory T (TRM) cells are a T-cell subset that resides at the site of prior antigen recognition to protect the body against reoccurring encounters. Besides their protective function,... Show moreTissue resident memory T (TRM) cells are a T-cell subset that resides at the site of prior antigen recognition to protect the body against reoccurring encounters. Besides their protective function, TRM cells have also been implicated in inflammatory disorders. TRM cells are characterized by the expression of CD69 and transcription factors Hobit (homolog of Blimp-1 [B lymphocyte-induced maturation protein 1] in T cells) and Blimp-1. As the majority of T cells in the arterial intima expresses CD69, TRM cells may contribute to the pathogenesis of atherosclerosis as well. Here, we aimed to assess the presence and potential role of TRM cells in atherosclerosis.To identify TRM cells in human atherosclerotic lesions, a single-cell RNA-sequencing data set was interrogated, and T-cell phenotypes were compared with that of integrated predefined TRM cells. The presence and phenotype of TRM in atherosclerotic lesions was corroborated using a mouse model that enabled tracking of Hobit-expressing TRM cells. To explore the function of TRM cells during atherogenesis, RAG1-/- (RAG1 deficient) LDLr-/- (low-density lipoprotein receptor knockout) mice received a bone marrow transplant from HobitKO/CREBlimp-1flox/flox mice, which exhibit abrogated TRM cell formation, whereafter the mice were fed a Western-type diet for 10 weeks.Human atherosclerotic lesions contained T cells that exhibited a TRM cell-associated gene signature. Moreover, a fraction of these T cells clustered together with predefined TRM cells upon integration. The presence of Hobit-expressing TRM cells in the atherosclerotic lesion was confirmed in mice. These lesion-derived TRM cells were characterized by the expression of CD69 and CD49α. Moreover, we demonstrated that this small T-cell subset significantly affects lesion composition, by reducing the amount of intralesional macrophages and increasing collagen content.TRM cells, characterized by the expression of CD69 and CD49α, constitute a minor population in atherosclerotic lesions and are associated with increased lesion stability in a Hobit and Blimp-1 knockout mouse model. Show less
Acute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is... Show moreAcute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is atherosclerosis, which is caused by the accumulation of lipids and inflammatory cells in the vessel wall, in so-called atherosclerotic plaques. Current therapies mainly target the disturbed lipid homeostasis, but recent clinical trials have shown a clear benefit in treating patients with anti-inflammatory drugs. However, more specific targeting is required to avoid unwanted side effects. In this thesis, we have generated a detailed atlas of all the cells present in human atherosclerotic plaques using a novel state-of-the-art technique called single-cell RNA sequencing. This data set can be applied as a powerful tool to select potential drug targets with a functional relevance for atherosclerosis. We showed that the majority of the immune cells in the human atherosclerotic plaque consisted of T cells. Subsequently, we identified a pro-inflammatory population of T cells that likely responds to a plaque-derived antigen, suggesting that atherosclerosis has an autoimmune-like component. Finally, we have applied our single-cell atlas to define and validate targets to intervene with the recruitment and activation of mast cells and other immune cells in atherosclerosis. Show less
Viral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been... Show moreViral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8+ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8+ T-cells in the atherosclerotic lesion.\nThe presence, clonality, tissue enrichment, and phenotype of virus-associated CD8+ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-β sequencing and single-cell T-cell receptor (α and β) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8+ T-cells can be activated through T-cell receptor stimulation in the atherosclerotic lesion, the immunopeptidome of human plaques was determined.\nVirus-associated CD8+ T-cells accumulated more in the atherosclerotic lesion (mean=2.0%), compared with patient-matched blood samples (mean=1.4%; P=0.05), and were more clonally expanded and tissue enriched in the atherosclerotic lesion in comparison with nonassociated CD8+ T-cells from the lesion. Single-cell T-cell receptor sequencing and flow cytometry revealed that these virus-associated CD8+ T-cells were phenotypically highly similar to other CD8+ T-cells in the lesion and that both exhibited a more activated phenotype compared with circulating T-cells. Interestingly, virus-associated CD8+ T-cells are unlikely to be activated through antigen-specific interactions in the atherosclerotic lesion, as no virus-derived peptides were detected on HLA-I in the lesion.\nThis study suggests that virus-specific CD8+ T-cells are tissue enriched in atherosclerotic lesions; however, their potential contribution to inflammation may involve antigen-independent mechanisms. 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
Ying, Z.X.; Eenige, R. van; Beerepoot, R.; Boon, M.R.; Kloosterhuis, N.J.; Sluis, B. van de; ... ; Kooijman, S. 2022
Activation of brown adipose tissue (BAT) with the 133-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is... Show moreActivation of brown adipose tissue (BAT) with the 133-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used 133-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)-and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipopro-tein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis. Show less
Background: The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different... Show moreBackground: The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different strategies: EVT with vs without carotid artery stenting (CAS). Methods: In this observational study, we included patients who had an acute ischaemic stroke undergoing EVT and a concomitant ipsilateral extracranial ICA stenosis of >= 50% or occlusion of presumed atherosclerotic origin, from the Dutch Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014-2017). The primary endpoint was a good functional outcome at 90 days, defined as a modified Rankin Scale score <= 2. Secondary endpoints were successful intracranial reperfusion, new clot in a different vascular territory, symptomatic intracranial haemorrhage, recurrent ischaemic stroke and any serious adverse event. Results: Of the 433 included patients, 169 (39%) underwent EVT with CAS. In 123/168 (73%) patients, CAS was performed before intracranial thrombectomy. In 42/224 (19%) patients who underwent EVT without CAS, a deferred carotid endarterectomy or CAS was performed. EVT with and without CAS were associated with similar proportions of good functional outcome (47% vs 42%, respectively; adjusted OR (aOR), 0.90; 95% CI, 0.50 to 1.62). There were no major differences between the groups in any of the secondary endpoints, except for the increased odds of a new clot in a different vascular territory in the EVT with CAS group (aOR, 2.96; 95% CI, 1.07 to 8.21). Conclusions: Functional outcomes were comparable after EVT with and without CAS. CAS during EVT might be a feasible option to treat the extracranial ICA stenosis but randomised studies are warranted to prove non-inferiority or superiority. Show less
Background The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different... Show moreBackground The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different strategies: EVT with vs without carotid artery stenting (CAS).Methods In this observational study, we included patients who had an acute ischaemic stroke undergoing EVT and a concomitant ipsilateral extracranial ICA stenosis of ≥50% or occlusion of presumed atherosclerotic origin, from the Dutch Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014–2017). The primary endpoint was a good functional outcome at 90 days, defined as a modified Rankin Scale score ≤2. Secondary endpoints were successful intracranial reperfusion, new clot in a different vascular territory, symptomatic intracranial haemorrhage, recurrent ischaemic stroke and any serious adverse event.Results Of the 433 included patients, 169 (39%) underwent EVT with CAS. In 123/168 (73%) patients, CAS was performed before intracranial thrombectomy. In 42/224 (19%) patients who underwent EVT without CAS, a deferred carotid endarterectomy or CAS was performed. EVT with and without CAS were associated with similar proportions of good functional outcome (47% vs 42%, respectively; adjusted OR (aOR), 0.90; 95% CI, 0.50 to 1.62). There were no major differences between the groups in any of the secondary endpoints, except for the increased odds of a new clot in a different vascular territory in the EVT with CAS group (aOR, 2.96; 95% CI, 1.07 to 8.21).Conclusions Functional outcomes were comparable after EVT with and without CAS. CAS during EVT might be a feasible option to treat the extracranial ICA stenosis but randomised studies are warranted to prove non-inferiority or superiority. Show less
Acute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from... Show moreAcute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from atherosclerosis, a progressive condition characterized by the accumulation of lipids, immune cells, and fibrous elements in large arteries. The pathogenesis of atherosclerosis involves complex interactions between a wide variety of cells, including monocytes, macrophages, neutrophils, and lymphocytes. It is essential to identify novel targets for therapeutic application in order to reduce the residual atherosclerotic cardiovascular disease risk in current and future patients. Recent studies have suggested that members of the protein arginine methyltransferase (PRMT) family can potentially serve as novel therapeutic targets for atherosclerosis because of their regulatory role in inflammation and metabolism. To validate the contribution of PRMTs in the progression of atherosclerosis, in the studies presented in this thesis we have investigated the effect of inhibition of PRMT functionality on atherosclerosis susceptibility in established atherosclerotic mouse models.To address the role of PRMTs in atherosclerosis, we therefore made use of specific PRMT inhibitors, i.e. TC-E 5003 for PRMT1 inhibition, TP-064 for PRMT4 inhibition, and GSK3326595 for PRMT5 inhibition, that thus far have primarily been applied in vivo in the context of cancer treatment. Show less
Background: We examined age differences in whole-heart volumes of non-calcified and calcified atherosclerosis by coronary computed tomography angiography (CCTA) of patients with future ACS. Methods... Show moreBackground: We examined age differences in whole-heart volumes of non-calcified and calcified atherosclerosis by coronary computed tomography angiography (CCTA) of patients with future ACS. Methods: A total of 234 patients with core-lab adjudicated ACS after baseline CCTA were enrolled. Atherosclerotic plaque was quantified and characterized from the main epicardial vessels and side branches on a 0.5 mm cross-sectional basis. Calcified plaque and non-calcified plaque were defined by above or below 350 Hounsfield units. Patients were categorized according to their age by deciles. Also, coronary artery calcium scores (CACS) were evaluated when available. Results: Patients were on average 62.2 +/- 11.5 years old. On the pre-ACS CCTA, patients showed diffuse, multi-site, predominantly non-obstructive atherosclerosis across all age categories, with plaque being detected in 93.5% of all ACS cases. The proportion calcified plaque from the total plaque burden increased significantly with older presentation (10% calcification in those <50 years, and 50% calcification in those >80 years old). Patients with ACS <50 years had remarkably lower atherosclerotic burden compared with older patients, but a high proportion of high risk markers such as low-attenuation plaque. CACS was >0 in 85% of the patients older than 50 years, and in 57% of patients younger than 50 years. Conclusion: The proportion of calcified plaque varied depending on patient age at the time of ACS. Only a small proportion of plaque was calcified when ACS occurred at <50 years old, while this increased gradually with older age. Purely non-calcified atherosclerotic plaque was not uncommon in patients <50 years. Show less
Schultz, J.; Hoogen, I.J. van den; Kuneman, J.H.; Graaf, M.A. de; Kamperidis, V.; Broersen, A.; ... ; Knuuti, J. 2022
Endothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed... Show moreEndothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed tomography angiography (CCTA)-based ESS in coronary arteries without atherosclerosis, and to assess factors affecting ESS values. CCTA images from patients with suspected coronary artery disease were analyzed to identify coronary arteries without atherosclerosis. Minimal and maximal ESS values were calculated for 3-mm segments. Factors potentially affecting ESS values were examined, including sex, lumen diameter and distance from the ostium. Segments were categorized according to lumen diameter tertiles into small (< 2.6 mm), intermediate (2.6-3.2 mm) or large (>= 3.2 mm) segments. A total of 349 normal vessels from 168 patients (mean age 59 +/- 9 years, 39% men) were included. ESS was highest in the left anterior descending artery compared to the left circumflex artery and right coronary artery (minimal ESS 2.3 Pa vs. 1.9 Pa vs. 1.6 Pa, p < 0.001 and maximal ESS 3.7 Pa vs. 3.0 Pa vs. 2.5 Pa, p < 0.001). Men had lower ESS values than women, also after adjusting for lumen diameter (p < 0.001). ESS values were highest in small segments compared to intermediate or large segments (minimal ESS 3.8 Pa vs. 1.7 Pa vs. 1.2 Pa, p < 0.001 and maximal ESS 6.0 Pa vs. 2.6 Pa vs. 2.0 Pa, p < 0.001). A weak to strong correlation was found between ESS and distance from the ostium (rho = 0.22-0.62, p < 0.001). CCTA-based ESS values increase rapidly and become widely scattered with decreasing lumen diameter. This needs to be taken into account when assessing the added value of ESS beyond lumen diameter in highly stenotic lesions. Show less
Currently immunomodulatory compounds are under investigation for use in patients with cardiovascular disease, caused by atherosclerosis. These trials, using recurrent cardiovascular events as... Show moreCurrently immunomodulatory compounds are under investigation for use in patients with cardiovascular disease, caused by atherosclerosis. These trials, using recurrent cardiovascular events as endpoint, require enrollment of large patient groups. We investigated the effect of key risk factors for atherosclerosis development, ageing and smoking, on the immune system, with the objective to identify biomarkers differentiating between human populations, and potentially serving as endpoints for future phase 1B trials with immunomodulatory compounds. Blood was collected from young healthy volunteers (aged 18-25 years, n=30), young smokers (18-25 years, n=20), elderly healthy volunteers (>60 years, n=20), heavy smokers (>45 years, 15 packyears, n=11) and patients with stable coronary artery disease (CAD) (>60 years, n=27). Circulating immune cell subsets were characterized by flow cytometry, and collected plasma was evaluated by proteomics (Olink). Clear ageing effects were observed, mostly illustrated by a lower level in CD8+ and naïve CD4+ and CD8+ T cells, with an increase in CD4+ and CD8+ effector memory T cells in elderly healthy volunteers compared to young healthy volunteers. Heavy smokers showed a more inflammatory cellular phenotype, especially a shift in Th1/Th2 ratio: higher Th1 and lower Th2 percentages compared to young healthy volunteers. A significant decrease in circulating atheroprotective oxLDL-specific IgM was found in patients with CAD compared to young healthy volunteers. Elevated pro-inflammatory and chemotactic proteins TREM1 and CCL11 were observed in elderly volunteers compared to young volunteers. In addition, heavy smokers had an increase in pro-inflammatory cytokine IL-6 and lysosomal protein LAMP3. These data show that ageing and smoking are associated with an inflammatory immunophenotype, and that heavy smokers or aged individuals may serve as potential populations for future clinical trials investigating immunomodulatory drugs targeted for cardiovascular disease. Show less
Brown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis... Show moreBrown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis in brown and beige adipocytes enhances the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in plasma to supply these adipocytes with fatty acids for oxidation. This process results in formation of TRL remnants that are removed from the circulation through binding of apolipoprotein E (ApoE) on their surface to the LDL receptor (LDLR) on hepatocytes, followed by internalization. Concomitantly, lipolytic processing of circulating TRLs leads to generation of excess surface phospholipids that are transferred to nascent HDLs, increasing their capacity for reverse cholesterol transport. Activation of thermogenic adipocytes thus lowers circulating triglycerides and non-HDL-cholesterol, while it increases HDL-cholesterol. The combined effect is protection from atherosclerosis development, which becomes evident in humanized mouse models with an intact ApoE-LDLR clearance pathway only, and is additive to the effects of classical lipid-lowering drugs including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. A large recent study revealed that the presence of metabolically active BAT in humans is associated with lower triglycerides, higher HDL-cholesterol and lower risk of cardiovascular diseases. This narrative review aims to provide leads for further exploration of thermogenic adipose tissue as a therapeutic target. To this end, we describe the latest knowledge on the role of BAT in lipoprotein metabolism and address, for example, the discovery of the beta(2)-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes. Show less
Aims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was... Show moreAims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. Methods and results: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P= 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). Conclusion: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.[GRAPHICS]. Show less
Ischemic heart disease is the most common cause of mortality worldwide. The pathophysiology of myocardial infarction relates to temporal changes of atherosclerotic plaque culminating in plaque... Show moreIschemic heart disease is the most common cause of mortality worldwide. The pathophysiology of myocardial infarction relates to temporal changes of atherosclerotic plaque culminating in plaque rupture, erosion or hemorrhage and the subsequent thrombotic response. Coronary computed tomographic angiography (CCTA) provides the ability to visualize and quantify plaque, and plaque progression can be measured on a per-patient basis by comparing findings of serial CCTA. The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry was established with the objective of identifying patterns of plaque progression in a large population. The registry comprises over 2000 patients with multiple CCTA scans performed at least two years apart. Unlike previous CCTA registries, a semi-automated plaque quantification technique permitting detailed analysis of plaque progression was performed on all patients with interpretable studies. Since the registry was established, 19 peer-reviewed publications were identified, and all are reviewed and summarized in this article. 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
The vascular system delivers oxygen and nutrients through the entire body. In addition, it enables distribution of hormones and immune cells. A proper functioning vascular system is important in... Show moreThe vascular system delivers oxygen and nutrients through the entire body. In addition, it enables distribution of hormones and immune cells. A proper functioning vascular system is important in preventing cardiovascular disease (CVD). In recent years, several risk factors, e.g. smoking and obesity, have been described. Also genetic variants have been shown to influence vascular function and thereby the risk on developing CVD.In this thesis the role of Neuroimmune Guidance Cues (NGCs) in the development of atherosclerosis, one of the main causes of CVD is investigated. The development of atherosclerosis is characterized by the deposition of fatty acids and immune cells in the vessel wall. With several experiments we have shown that NGCs play an important role in the vessel wall and regulate atherosclerosis-related processes. We show that PLXNA4 regulates endothelial permeability, while the Eph receptor B2 regulates migration of monocytes through the vessel. In addition, we have shown that genetic variants in Eph receptor B4, EphrinB2 and Netrin-1 can modulate atherosclerosis-related processes and thereby could influence the development of CVD.The results shown here give us new insights in the function of the vascular system and provide novel targets to treat and/or prevent CVD. Show less
Mahe, G.; Brodmann, M.; Capodanno, D.; Ceriello, A.; Cuisset, T.; Delgado, V.; ... ; Valensi, P. 2022
Aims: This survey aimed to evaluate the current management and screening of coronary artery disease and peripheral artery disease in people with type 2 diabetes mellitus (T2DM) in Europe, utilizing... Show moreAims: This survey aimed to evaluate the current management and screening of coronary artery disease and peripheral artery disease in people with type 2 diabetes mellitus (T2DM) in Europe, utilizing the 2013 ESC/EASD (European Society of Cardiology/European Association for the Study of Diabetes) guidelines as a benchmark. Methods: The PADDIA/CADDIA survey is a European medical research collaboration targeting cardiologists, vascular physicians, diabetologists and general practitioners from Austria, Belgium, France, Germany, Italy, Netherlands and United Kingdom. Results: The questionnaire was completed by sixty-three physicians, of whom 75% declared assessing the cardiovascular risk of people with T2DM mostly without using a risk score (59%). More than 90% of the panel, check HbA1c, blood pressure and low-density lipoprotein cholesterol targets in their patients with T2DM and coronary or peripheral artery disease. For 94% the presence of T2DM influence their patients' management, by optimizing blood glucose, blood pressure and low-density lipoprotein cholesterol control. Only 37% considered screening for lower extremity peripheral artery disease among their T2DM patients and 35% among those with cardiovascular disease. Conclusions: Physicians mostly follow the ESC/EASD 2013 guidelines, but when it comes to screening for additional conditions including coronary artery disease or peripheral artery disease, or intensifying the antithrombotic regimen there is need for better guidance. (C) 2022 Elsevier B.V. All rights reserved. Show less
Signaling through the coinhibitory programmed death (PD)-1/PD-L1 pathway regulates T cell responses and can inhibit ongoing immune responses. Inflammation is a key process in the development of... Show moreSignaling through the coinhibitory programmed death (PD)-1/PD-L1 pathway regulates T cell responses and can inhibit ongoing immune responses. Inflammation is a key process in the development of atherosclerosis, the underlying cause for the majority of cardiovascular diseases. Dampening the excessive immune response that occurs during atherosclerosis progression by promoting PD-1/PD-L1 signaling may have a high therapeutic potential to limit disease burden. In this study we therefore aimed to assess whether an agonistic PD-1 antibody can diminish atherosclerosis development.Ldlr-/- mice were fed a western-type diet (WTD) while receiving 100 μg of an agonistic PD-1 antibody or control vehicle twice a week. Stimulation of the PD-1 pathway delayed the WTD-induced monocyte increase in the circulation up to 3 weeks and reduced T cell activation and proliferation. CD4+ T cell numbers in the atherosclerotic plaque were reduced upon PD-1 treatment. More specifically, we observed a 23% decrease in atherogenic IFNγ-producing splenic CD4+ T cells and a 20% decrease in cytotoxic CD8+ T cells, whereas atheroprotective IL-10 producing CD4+ T cells were increased with 47%. Furthermore, we found an increase in regulatory B cells, B1 cells and associated atheroprotective circulating oxLDL-specific IgM levels in agonistic PD-1-treated mice. This dampened immune activation following agonistic PD-1 treatment resulted in reduced atherosclerosis development (p < 0.05).Our data show that stimulation of the coinhibitory PD-1 pathway inhibits atherosclerosis development by modulation of T- and B cell responses. These data support stimulation of coinhibitory pathways as a potential therapeutic strategy to combat atherosclerosis. Show less
