P728Subclinical atherosclerosis and its progression are modulated by perilipin-2 through a feed-forward loop between LXR and autophagy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Ehrenborg ◽  
P Saliba Gustafsson ◽  
M Pedrelli ◽  
K Gertow ◽  
S Pourteymour ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
Feed Forward ◽  
Feed Forward Loop ◽  
Beneficial Effects ◽  
Media Thickness ◽  
Primary Monocyte ◽  
Perilipin 2 ◽  
Autophagy Activity

Abstract Background Hyperlipidemia is a major risk factor for cardiovascular disease and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial for atherosclerosis development. Purpose We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype, or from buffy coats from the our University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and 30 months follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant we show that this variant increases autophagy activity, cholesterol efflux, and a controlled inflammatory response. Through extensive mechanistic studies we demonstrate that increase in autophagy activity is accompanied with an increase in LXR activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis. Acknowledgement/Funding The Swedish Research Council, Swedish Heart-Lung Foundation, Marianne and Marcus Wallenberg's Foundation, Swedish Medical Society

Subclinical atherosclerosis in children and adolescents with congenital heart disease

2020 ◽  
pp. 1-8
Author(s):  
Silvia M. Cardoso ◽  
Michele Honicky ◽  
Yara M. F. Moreno ◽  
Luiz R. A. de Lima ◽  
Matheus A. Pacheco ◽  
...  
Keyword(s):  
Risk Factors ◽  
Congenital Heart Disease ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Clinical Characteristics ◽  
Congenital Heart ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Media Thickness

Abstract Background: Subclinical atherosclerosis in childhood can be evaluated by carotid intima-media thickness, which is considered a surrogate marker for atherosclerotic disease in adulthood. The aims of this study were to evaluate carotid intima-media thickness and, to investigate associated factors. Methods: Cross-sectional study with children and adolescents with congenital heart disease (CHD). Socio-demographic and clinical characteristics were assessed. Subclinical atherosclerosis was evaluated by carotid intima-media thickness. Cardiovascular risk factors, such as physical activity, screen time, passive smoke, systolic and diastolic blood pressure, waist circumference, dietary intake, lipid parameters, glycaemia, and C-reactive protein, were also assessed. Factors associated with carotid intima-media thickness were analysed using multiple logistic regression. Results: The mean carotid intima-media thickness was 0.518 mm and 46.7% had subclinical atherosclerosis (carotid intima-media thickness ≥ 97th percentile). After adjusting for confounding factors, cyanotic CHD (odds ratio: 0.40; 95% confidence interval: 0.20; 0.78), cardiac surgery (odds ratio: 3.17; 95% confidence interval: 1.35; 7.48), and be hospitalised to treat infections (odds ratio: 1.92; 95% confidence interval: 1.04; 3.54) were associated with subclinical atherosclerosis. Conclusion: Clinical characteristics related to CHD were associated with subclinical atherosclerosis. This finding suggests that the presence of CHD itself is a risk factor for subclinical atherosclerosis. Therefore, the screen and control of modifiable cardiovascular risk factors should be made early and intensively to prevent atherosclerosis.

scholarly journals Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

2021 ◽  
Author(s):  
Eliana Portilla-Fernández ◽  
Shih-Jen Hwang ◽  
Rory Wilson ◽  
Jane Maddock ◽  
W. David Hill ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Dna Methylation ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Association Studies ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Media Thickness

AbstractCommon carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = −0.0264, p value = 3.5 × 10–8) in the discovery panel and was replicated in replication panel (beta = −0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

scholarly journals AB0258 CAROTID INTIMA-MEDIA THICKNESS AND SERUM BIOMARKERS IN PARAGUAYAN PATIENTS WITH RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1428.2-1428
Author(s):  
V. Valinotti ◽  
A. Paats ◽  
R. Acosta ◽  
L. Roman ◽  
I. Acosta-Colman ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Disease Duration ◽  
Subclinical Atherosclerosis ◽  
High Sensitivity ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Serum Biomarkers ◽  
Carotid Plaques ◽  
Media Thickness ◽  
Hs Crp

Background:The mechanism of increased cardiovascular risk in RA is not well understood and is independent of traditional CV risk factors. Intima-media thickness of the common carotid wall measured by ultrasonogram is a safe and useful biomarker of early stage atherosclerosis that correlates with coronary involvement; and it correlates with severity and duration of disease. Several studies have shown a relationship between inflammation markers, endothelial dysfunction markers, and carotid involvement. (1)Objectives:To determine the presence of inflammation biomarkers and its relationship with subclinical atherosclerosis measured by carotid ultrasound, and with the clinical characteristics in patients with established Rheumatoid Arthritis (RA)Methods:Descriptive, cross sectional, prospective study, in a Paraguayan cohort of patients with RA meeting ACR/EULAR2010 criteria. This study had two phases: the first one, included a standardized questionnaire according to the variables included in the Cardiovascular Risk project (PINV15-0346), from the National Sciences and Technology Council (CONACYT), and physical examination; the second one included laboratory sample collection performed by a specialized laboratory for serum biomarkers measurement for cardiovascular risk prediction (i.e endothelin, alpha-TNF, E-selectin, homocysteine, apolipoprotein, fibrinogen, and high sensitivity-CRP levels) and carotid ultrasound evaluation by a trained specialist, to evaluate subclinical atherosclerosis. Subclinical atherosclerosis was defined as carotid intima-media thickness (CIMT) >0,9mm and/or presence of carotid plaques. All patients signed informed consent. SPSS 23rd version was used for data analysis. Quantitative variables were presented as means and qualitative as frequencies. Chi square test was performed for comparisons between dichotomous variables and t Student for continuous, and p ≤ 0.05 for statistical significance.Results:100 patients were included, 87% were women, mean disease duration 130.9±102.64 months, 77% were RF positive, and 84.4% were ACPA positive, 43.4% had bone erosions, mean ESR-DAS28 was 3,42±1,1; 30% had remission criteria. 39% had extra-articular manifestations.Elevated serum biomarkers were found: fibrinogen >400 mg/dL 88.2%, high sensitivity-CRP (hs-CRP) >5mg/dL 42.9%, endothelin >2 ng/mL 20%, alpha-TNF >15,6 pg/mL 13.1%, E-selectin >79,2 ng/mL 6%. 25.3% had CIMT >0,9 mm and mean CIMT was 0.68±0.25mm. 27.14% had carotid plaques. Patients with CIMT>1mm had higher frequency of family history of arterial hypertension (p=0.006), greater mean disease duration (p=0.0007), hip circumference (p=0.014), blood pressure (SBP p=0.038, DBP p=0.027), HAQ levels (p=0,019) and hs-CRP levels (p=0.013), also lower mean height (p=0,04); while carotid plaques were related to higher homocysteine (p=0.026) and hs-CRP levels (p=0.024).Conclusion:A considerable percentage of patients had subclinical atherosclerosis. Patients with CIMT>0,9mm had a longer disease duration, higher HAQ levels, hip circumference, as well as higher BP. High levels of hs-CRP were more frequently related to the presence of subclinical atherosclerosisReferences:[1]Aday, A. targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease. Frontiers in cardiovascular medicine. 2019. 6:16.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403155/pdf/fcvm-06-00016.pdfDisclosure of Interests:None declared

scholarly journals AB0186 AT WHAT LEVEL SHOULD WE MEASURE INTIMA-MEDIA THICKNESS IN RHEUMATOID ARTHRITIS?

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1117.3-1118
Author(s):  
L. Nacef ◽  
H. Ferjani ◽  
H. Riahi ◽  
K. Maatallah ◽  
Y. Mabrouk ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Internal Carotid ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
University Hospital ◽  
External Carotid ◽  
Media Thickness ◽  
The Mean ◽  
The Right ◽  
Score Index

Background:Rheumatoid arthritis (RA) is chronic inflammatory rheumatism characterized by an independent cardiovascular (CV) risk. The screening of carotid intima-media thickness (IMT) in the common carotid artery appears to be a marker of atherosclerosis and is used as a specific tool for CV risk assessment.Objectives:The main of this study was to determine the most associated US sites with CV risk in RA.Methods:The present study is a prospective study conducted on Tunisian RA patients in rheumatology department of Mohamed Kassab University Hospital (March and December 2020). The characteristics of the patients and those of the disease were collected. The measurement of cIMTwas done using high-resolution B-mode carotid US with a Philips machine with the patient in supine position, according to AmericanSociety of Echocardiography guidelines.The carotid bulb below itsbifurcation and the internal and external carotid arteries were evaluated bilaterally with gray scale, spectral and color Doppler ultra-sonography using proprietary software for carotid arterymeasurements.IMT was measured using the two inner layers of the commoncarotid artery and an increased IMT was defined as ≥0.9 mm. The CV risk at 10 years was calculated by the SCORE index.Results:Forty-seven patients were collected, of which 78.7% were women. The mean age was 52.5 ±11.06 years. The rheumatoid factor (RF) was positive in 57.8% of cases, and anti-citrullinated peptide antibodies (ACPA) were positive in 62.2% of cases. RA was erosive in 81.6% of cases. Hypertension (hypertension) was present in 14.9% of patients and diabetes in 12.8% of patients. Nine patients were active smokers. The mean IMT in the left common carotid (LCC) was 0.069 ±0.015, in the left internal carotid (LIC) was 0.069 ±0.015, in the left external carotid (LEC) was 0.060 ±0.023. The mean IMT was 0.068 ±0.01 in the right common carotid (RCC), 0.062 ±0.02 in the right internal carotid (RIC), and 0.060 ±0.016 in the right external carotid (REC). The mean SCORE index of CV risk was 2±2.81 [0-11.6]. CV risk was significantly associated with the IMTs for LIC (p=0.029; r=0.374), LEC (p=0.04; r=0.480), and REC (p=0.016; r=0.408). No association was found between the IMT in the LCC (p=0,361; r=0,162), neither in the RCC (p=0,438; r=0,140) nor the RIC (p=0,670; r=0,077).Conclusion:In our study, IMT is strongly associated with score index, especially in carotid bifurcation. However, IMT measured in common carotid does not reflect a cardiovascular risk at 10-years.References:[1]S. Gunter and al. Arterial wave reflection and subclinical atherosclerosis in rheumatoid arthritis. Clinical and Experimental Rheumatology 2018; 36: Clinical E.xperimental.[2]Aslan and al. Assessment of local carotid stiffness in seronegative and seropositive rheumatoid arthritis. SCANDINAVIAN CARDIOVASCULAR JOURNAL, 2017.[3]Martin I. Wah-Suarez and al, Carotid ultrasound findings in rheumatoid arthritis and control subjects: A case-control study. Int J Rheum Dis. 2018;1–7.Disclosure of Interests:None declared

Abstract 17913: Inhibition of CETP by Dalcetrapib Results in a Modest Increase in Cholesterol Efflux Capacity Associated With an Increase in Large HDL Particles, but Does Not Impact Carotid Intima-Media Thickness in a dal-PLAQUE-2 Substudy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
David Rhainds ◽  
Marie Boule ◽  
Sonia Alem ◽  
Mathieu R Brodeur ◽  
Daniel Charpentier ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Cholesterol Efflux ◽  
Hdl Cholesterol ◽  
Intima Media Thickness ◽  
Phase Iii ◽  
Plaque Burden ◽  
Cholesterol Efflux Capacity ◽  
Media Thickness ◽  
One Year ◽  
Neutral Effect

Inhibition of cholesteryl ester transfer protein (CETP) is an approach aiming at raising HDL-cholesterol levels and reducing cardiovascular risk. The dal-PLAQUE-2 phase III study recruited 988 subjects with stable coronary artery disease. Its primary objective was to evaluate the effect of dalcetrapib on the progression of carotid atherosclerotic disease measured by intima-media thickness after one year of therapy. As dalcetrapib showed a neutral effect on cardiovascular risk in the dal-OUTCOMES study, our objective was to evaluate its effect on cIMT and markers of HDL mass, lipoprotein subclass distribution and HDL function. All subjects from dal-PLAQUE-2 who had provided serum samples at baseline and one year were included in our substudy of 193 subjects on placebo and 186 subjects on dalcetrapib. Comparisons between groups at one year were made by ANCOVA after adjustment for baseline levels. No significant differences between groups for all variables considered were observed at baseline. Dalcetrapib reduced CETP activity as measured by a fluorescent method by 30% after 1 year (p<0.001), which resulted in increases in HDL-cholesterol and apoA-I levels by 32% and 11%, respectively (both p<0.001). Dalcetrapib markedly increased the concentration of large HDL particles measured by NMR profiling (+59%, p<0.001), at the expense of small HDL particles (-9.5%, p<0.001). Cholesterol efflux capacity of serum was measured from J774 macrophages under basal conditions and after cAMP stimulation. Dalcetrapib increased basal and stimulated efflux by 7.1% and 5.5% (both p<0.001), but was without effect on the ABCA1-dependent component (p=0.26). Despite these effects, dalcetrapib had no impact on mean and maximal cIMT (p=0.98 and p=0.85). While the change in cIMT was inversely correlated with basal cholesterol efflux in the placebo group (Spearman r=-0.163, p<0.05), such a relationship was not found in the dalcetrapib group. Moreover, the change in total HDL particles concentration was inversely correlated with change in cIMT (r=0.181, p<0.05) in the placebo arm only. In conclusion, dalcetrapib raised HDL-C and larger HDL, but this had minimal effects on cholesterol efflux capacity of patients’ serum and had a neutral effect on carotid artery plaque burden.

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