27,548 research outputs found

    Β-carotene promotes atherosclerosis resolution and alleviates liver inflammation in a reversible murine model of atherosclerosis: A potential role of regulatory T cells

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    Background: β-carotene has several health benefits on lipid metabolism, most of which are mediated through its provitamin A activity. Our laboratory has recently shown that β-carotene conversion to vitamin A is associated with reduced circulating cholesterol levels in mice and humans. Objective: To study the effect of β-carotene on atherosclerosis regression and hepatic inflammation. Methods: We utilized various animal models to study atherosclerosis regression: In our first model, we used weekly injections of an antisense oligonucleotide targeting the expression of the low-density lipoprotein receptor (LDLR ASO). To facilitate the development of atherosclerotic lesions, we fed these mice a Western diet (0.3% cholesterol, 41% of calories from fat) deficient in vitamin A (WD-VAD) for 16 weeks, after which we harvested the baseline group. The remaining mice underwent regression by stopping the LDLR ASO injections and injecting them once with LDLR SO, which binds and deactivates LDLR ASO. To study the role of β-carotene on atherosclerosis regression, we maintained a subset of mice on the same diet (WD-VAD), and another subset fed with a WD-VAD supplemented with 50 mg/kg of β-carotene (WD-β-carotene) for three weeks. To test the implication of regulatory T cells (Tregs) in β-carotene-induced atherosclerosis regression, we treated a group of mice with an anti-CD25 monoclonal antibody to deplete Tregs during regression. For all experiments, aortic roots, plasma, and tissues were collected and analyzed using morphometric and biochemical methods. Liver samples were harvested for RNA sequencing and histological analyses. Results: Baseline mice showed an increase in cholesterol levels in comparison to all regression groups, independently of the presence of β-carotene in the diet. These changes occurred independently of alterations in body weight. For the LDLR ASO model, histological analyses of aortic roots failed to show differences in atherosclerotic lesion area between groups, although we observed a reduction in the macrophage content in both regression groups that was more pronounced in WD-β-carotene-fed mice; baseline vs regression-VAD (~30%, P=0.053), and baseline vs regression-β-carotene (~42%, P<0.005). Collagen content in plaques, an indicator of plaque stability in humans, showed an increase in both regression groups; baseline vs regression-VAD (~217%, P <0.005), and baseline vs regression-β-carotene (~308%, P<0.0001). Lastly, anti-CD25 infusions decreased Tregs content in plasma and spleen. We also analyzed the liver using RNA sequencing and immunostaining. We found that the baseline mice showed a significant increase in hepatic macrophage accumulation in comparison to both regression groups. However, β-carotene showed a more pronounced effect on reducing hepatic inflammation compared to VAD. Conclusion: β-carotene enhances atherosclerosis resolution, as observed by a reduction in plaque macrophage content accompanied with an increase in collagen content. Atherosclerosis resolution is associated with a reduction in hepatic macrophage content and β-carotene enhances these positive effects.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste

    When immunology meets cholesterol metabolism in atherosclerosis... A match for immune-inflammatory and lipid metabolic disease?

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    Atherosclerosis is a chronic inflammatory disease characterized by a subendothelial accumulation of lipids and the formation of a plaque which rupture is the principal cause of cardiovascular events. This process is largely driven by the immune system and high circulating low-density lipoprotein (LDL) levels. Although many studies have demonstrated the effects of hypercholesteremia on inflammatory pathways, only a few studies specifically investigated the effects of immunity on lipid metabolism. PCSK9 is a key target for the treatment of hypercholesterolemia. PCSK9 inhibitors have been shown to reduce LDL and diminish atherosclerosis through LDL receptor (LDLR) regulation. However, the specific mechanisms regulating LDLR endosomal recycling are not completely revealed. Toll-interacting protein (Tollip) is an adaptor protein, initially described as an NF-κB signaling regulator, controlling the turnover of ubiquitinated receptors through endosomal trafficking. The present thesis revealed that Tollip controls LDL levels through posttranslational modulation of LDLR. Bone marrow-derived macrophages and hepatocytes from ApoE-/-Tollip-/- mice exhibited lower LDLR expression, whereas ApoE-/-Tollip-/- mice fed high cholesterol diet (HCD) had significantly elevated cholesterol levels and increased atherosclerotic plaques in comparison with ApoE-/- mice. These findings point that LDLR expression regulation is a key process involved in the atheroprotective effects of Tollip. Moreover, the present work demonstrated that Tollip regulates the recycling of LDLR from the endosome back to the cell surface and/or directs LDLR to autophagy-mediated degradation. Taken together our data highlight the role of Tollip, a mediator of low-grade inflammation, as an autophagic regulator of LDLR expression. The second aspect of this thesis aims to reveal how TGF-β-producing B (BTGFβ1-/-) cells direct the immune response in atherosclerosis and impact cholesterol metabolism. Several studies have demonstrated that BTGFβ1-/- cells can suppress the immune responses in various diseases. However, the role of BTGFβ1-/- cells in atherosclerosis is largely unexplored. ApoE-/-BTGFβ1-/- mice fed HCD exhibited a pronounced increase of plasma B cells in the spleen, lymph nodes, and aorta, while immunoglobulins IgG1-oxLDL-specific levels raised significantly compared to ApoE-/- mice. In addition to direct immune-mediated effects, ApoE-/-BTGFβ1-/- mice had lower LDL and total cholesterol plasma levels, smaller atherosclerotic plaque size, and improved plaque stability compared to ApoE-/- mice. This atheroprotective effect could be partially explained by increased expression of ABCG1 in foam cells and in the liver, essential for reverse cholesterol transport; and by the reduction of scavenger receptors expression, promoting a decrease in foam cell formation. This is the first study to demonstrate that TGF-β-specific B cell deficiency in ApoE-/- mice has a beneficial effect on atherosclerotic disease and regulates plasma levels of cholesterol. The present work demonstrates how immunity affects lipid metabolism, resulting in pronounced effects on atherosclerosis severity.</p

    Predviđanje srčanog udara primjenom simulacije međudjelovanja između fluida i deformabilnog tijela

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    Cardiovascular diseases are the leading cause of death in modern civilization, which result from insufficient coronary blood flow. The majority of them can be attributed to atherosclerosis, which causes the development of plaques that protrude into the vessel lumens and either block or partially block blood flow. The partial blockage leads to the development of collateral coronary circulation that can eliminate any symptoms of cardiac dysfunction to some degree. When the collateral circulation is insufficient, the heart muscle becomes severely limited in its work output, resulting in a heart attack. The main focus of this thesis is to simulate the nonlinear dynamics of the atherosclerotic coronary artery as a tool to predict the occurrence of a heart attack. A three-dimensional fluid-structure interaction (FSI) model is reconstructed based on the patient-specific computerized tomography (CT) scans and simulated via the finite volume method using OpenFOAM® for the determination of regions with the highest von Misses and shear stresses. The arterial wall is assumed to be rigid, while the accumulated plaque is modeled as a hyperelastic incompressible body. The fluid model incorporates transient isothermal and laminar blood flow with simplified geometry and realistic hemodynamic conditions, where blood is modeled as a Newtonian and incompressible fluid. The atherosclerotic plaque is modeled as a homogeneous solid body with mixed material properties such as smooth muscle cells, collagen, and lipids. These are the main constituents of the plaque body, all significantly different in their stiffness level, which may be the main cause of plaque rupture and initiation of myocardial infarction. In the future, the study of arterial blood flow will lead to the prediction of individual hemodynamic flows in any patient, the development of diagnostic tools to quantify the disease, and the design of devices that mimic or alter blood flow. This field is rich in challenging problems in fluid mechanics involving three-dimensional, pulsating flows at the edge of turbulence.Bolesti krvožilnog sustava predstavljaju glavni uzrok smrti u suvremeno dobra, a posljedica su nedostatnog koronarnog protoka krvi. Većina ih se može pripisati aterosklerozi koja uzrokuje stvaranje aterosklerotskog plaka, koji strši u lumen krvnih žila i djelomično ili posve priječi protok krvi. Djelomično začepljenje dovodi do razvoja kolateralne koronarne cirkulacije koja u određenoj mjeri može ukloniti simptome srčane disfunkcije. Kada i kolateralna cirkulacija nije dovoljna, sposobnost srčanog mišića za obavljanje rada se značajno smanjuje, što s vremenom dovodi do srčanog udara. Glavni cilj ovo rada je simulacija nelinearnog ponašanja aterosklerotične koronarne arterije koja može poslužiti kao alat za predviđanje srčanog udara. Trodimenzionalni model međudjelovanja fluida i čvrstog tijela (FSI) rekonstruiran je na temelju CT skenova, specifičnog za pojedinog pacijenta, i simuliran metodom kontrolnih volumena koristeći programski paket OpenFOAM® za određivanje područja s najvećim normalnim i posmičnim naprezanjima. Pretpostavljena je kruta arterijska stijenka, dok je nakupljeni plak modeliran kao hiperelastično nestlačivo tijelo. Model fluida uključuje nestacionarni izotermni i laminarni protok krvi s pojednostavljenom geometrijom i realnim hemodinamičkim uvjetima, dok je krv modelirana kao nestlaičivi i newtonski fluid. Aterosklerotski plak je modeliran kao homogeno čvrsto tijelo s miješanim svojstvima materijala kao što su glatke mišićne stanice, kolagen i lipidi. Oni predstavljaju glavne slojeve plaka, a njihova značajna razlika u krutosti može biti jedan od glavnih uzroka njegova puknuća, a samim time i infarkta miokarda. U budućnosti će proučavanje arterijskog krvotoka dovesti do predviđanja pojedinačnih hemodinamičkih tokova kod pacijenata, razvoja dijagnostičkih alata za kvantificiranje bolesti i dizajna uređaja koji oponašaju ili mijenjaju protok krvi. Ovo polje je bogato izazovnim problemima u mehanici fluida koji uključuju trodimenzionalne, pulsirajuće tokove na rubu turbulencije

    Predviđanje srčanog udara primjenom simulacije međudjelovanja između fluida i deformabilnog tijela

    No full text
    Cardiovascular diseases are the leading cause of death in modern civilization, which result from insufficient coronary blood flow. The majority of them can be attributed to atherosclerosis, which causes the development of plaques that protrude into the vessel lumens and either block or partially block blood flow. The partial blockage leads to the development of collateral coronary circulation that can eliminate any symptoms of cardiac dysfunction to some degree. When the collateral circulation is insufficient, the heart muscle becomes severely limited in its work output, resulting in a heart attack. The main focus of this thesis is to simulate the nonlinear dynamics of the atherosclerotic coronary artery as a tool to predict the occurrence of a heart attack. A three-dimensional fluid-structure interaction (FSI) model is reconstructed based on the patient-specific computerized tomography (CT) scans and simulated via the finite volume method using OpenFOAM® for the determination of regions with the highest von Misses and shear stresses. The arterial wall is assumed to be rigid, while the accumulated plaque is modeled as a hyperelastic incompressible body. The fluid model incorporates transient isothermal and laminar blood flow with simplified geometry and realistic hemodynamic conditions, where blood is modeled as a Newtonian and incompressible fluid. The atherosclerotic plaque is modeled as a homogeneous solid body with mixed material properties such as smooth muscle cells, collagen, and lipids. These are the main constituents of the plaque body, all significantly different in their stiffness level, which may be the main cause of plaque rupture and initiation of myocardial infarction. In the future, the study of arterial blood flow will lead to the prediction of individual hemodynamic flows in any patient, the development of diagnostic tools to quantify the disease, and the design of devices that mimic or alter blood flow. This field is rich in challenging problems in fluid mechanics involving three-dimensional, pulsating flows at the edge of turbulence.Bolesti krvožilnog sustava predstavljaju glavni uzrok smrti u suvremeno dobra, a posljedica su nedostatnog koronarnog protoka krvi. Većina ih se može pripisati aterosklerozi koja uzrokuje stvaranje aterosklerotskog plaka, koji strši u lumen krvnih žila i djelomično ili posve priječi protok krvi. Djelomično začepljenje dovodi do razvoja kolateralne koronarne cirkulacije koja u određenoj mjeri može ukloniti simptome srčane disfunkcije. Kada i kolateralna cirkulacija nije dovoljna, sposobnost srčanog mišića za obavljanje rada se značajno smanjuje, što s vremenom dovodi do srčanog udara. Glavni cilj ovo rada je simulacija nelinearnog ponašanja aterosklerotične koronarne arterije koja može poslužiti kao alat za predviđanje srčanog udara. Trodimenzionalni model međudjelovanja fluida i čvrstog tijela (FSI) rekonstruiran je na temelju CT skenova, specifičnog za pojedinog pacijenta, i simuliran metodom kontrolnih volumena koristeći programski paket OpenFOAM® za određivanje područja s najvećim normalnim i posmičnim naprezanjima. Pretpostavljena je kruta arterijska stijenka, dok je nakupljeni plak modeliran kao hiperelastično nestlačivo tijelo. Model fluida uključuje nestacionarni izotermni i laminarni protok krvi s pojednostavljenom geometrijom i realnim hemodinamičkim uvjetima, dok je krv modelirana kao nestlaičivi i newtonski fluid. Aterosklerotski plak je modeliran kao homogeno čvrsto tijelo s miješanim svojstvima materijala kao što su glatke mišićne stanice, kolagen i lipidi. Oni predstavljaju glavne slojeve plaka, a njihova značajna razlika u krutosti može biti jedan od glavnih uzroka njegova puknuća, a samim time i infarkta miokarda. U budućnosti će proučavanje arterijskog krvotoka dovesti do predviđanja pojedinačnih hemodinamičkih tokova kod pacijenata, razvoja dijagnostičkih alata za kvantificiranje bolesti i dizajna uređaja koji oponašaju ili mijenjaju protok krvi. Ovo polje je bogato izazovnim problemima u mehanici fluida koji uključuju trodimenzionalne, pulsirajuće tokove na rubu turbulencije

    Biomarkers in acute ischemic stroke

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    Impact of puberty, sex determinants and chronic inflammation on cardiovascular risk in young people

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    Worrying trends of increased cardiovascular disease (CVD) risk in children, adolescents and young people in the Modern Era have channelled research and public health strategies to tackle this growing epidemic. However, there are still controversies related to the dynamic of the impact of sex, age and puberty on this risk and on cardiovascular health outcomes later in life. In this comprehensive review of current literature, we examine the relationship between puberty, sex determinants and various traditional CVD-risk factors, as well as subclinical atherosclerosis in young people in general population. In addition, we evaluate the role of chronic inflammation, sex hormone therapy and health-risk behaviours on augmenting traditional CVD-risk factors and health outcomes, ultimately aiming to determine whether tailored management strategies for this age group are justified

    A computational framework for pharmaco-mechanical interactions in arterial walls using parallel monolithic domain decomposition methods

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    A computational framework is presented to numerically simulate the effects of antihypertensive drugs, in particular calcium channel blockers, on the mechanical response of arterial walls. A stretch-dependent smooth muscle model by Uhlmann and Balzani is modified to describe the interaction of pharmacological drugs and the inhibition of smooth muscle activation. The coupled deformation-diffusion problem is then solved using the finite element software FEDDLib and overlapping Schwarz preconditioners from the Trilinos package FROSch. These preconditioners include highly scalable parallel GDSW (generalized Dryja-Smith-Widlund) and RDSW (reduced GDSW) preconditioners. Simulation results show the expected increase in the lumen diameter of an idealized artery due to the drug-induced reduction of smooth muscle contraction, as well as a decrease in the rate of arterial contraction in the presence of calcium channel blockers. Strong and weak parallel scalability of the resulting computational implementation are also analyzed

    Statins influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis

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    Objectives: Cholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-β HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-β HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA). Methods: Evaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol. Results: ABCA1-CEC negatively correlated with ABCG1-CEC (r = −0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20–3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65–1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61–0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23–0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18–3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and < 0.001 respectively). Moreover, ABCA1-CEC (per SD) associated with greater partially/fully-calcified plaque progression (adjusted odds ratio 3.07 [95%CI 1.20–7.86]) only in patients not exposed to statins during follow-up (p-for-interaction = 0.009). Conclusion: In patients with RA, higher ABCA1-CEC may reflect a proatherogenic state, associated with enhanced cardiovascular risk. Statin use may unmask the protective impact of ABCA1-mediated cholesterol efflux on plaque formation, progression and cardiovascular risk

    Percutaneous angioplasty and/or stenting versus aggressive medical therapy in patients with symptomatic intracranial atherosclerotic stenosis: a 1-year follow-up study

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    BackgroundSymptomatic intracranial atherosclerotic stenosis (sICAS) is one of the common causes of ischemic stroke. However, the treatment of sICAS remains a challenge in the past with unfavorable findings. The purpose of this study was to explore the effect of stenting versus aggressive medical management on preventing recurrent stroke in patients with sICAS.MethodsWe prospectively collected the clinical information of patients with sICAS who underwent percutaneous angioplasty and/or stenting (PTAS) or aggressive medical therapy from March 2020 to February 2022. Propensity score matching (PSM) was employed to ensure well-balanced characteristics of two groups. The primary outcome endpoint was defined as recurrent stroke or transient ischemic attack (TIA) within 1 year.ResultsWe enrolled 207 patients (51 in the PTAS and 156 in the aggressive medical groups) with sICAS. No significant difference was found between PTAS group and aggressive medical group for the risk of stroke or TIA in the same territory beyond 30 days through 6 months (P = 0.570) and beyond 30 days through 1 year (P = 0.739) except for within 30 days (P = 0.003). Furthermore, none showed a significant difference for disabling stroke, death and intracranial hemorrhage within 1 year. These results remain stable after adjustment. After PSM, all the outcomes have no significant difference between these two groups.ConclusionThe PTAS has similar treatment outcomes compared with aggressive medical therapy in patients with sICAS across 1-year follow-up
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