Direct association between diet and the stability of human atherosclerotic plaque.
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ABSTRACT:
SUBMITTER: Goncalves I
PROVIDER: S-EPMC4614889 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:BackgroundImmune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events.MethodsThe study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls matched by age, a history of cardiovascular events, and cancer type. In a second design, a case-crossover analysis was performed with an at-risk period defined as the 2-year period after and the control period as the 2-year period before treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. All study measures and outcomes were blindly adjudicated.ResultsIn the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (hazard ratio, 3.3 [95% CI, 2.0-5.5]; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5-6.5]; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids.ConclusionsCardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk before, during, and after treatment should be considered among patients on an ICI.
| S-EPMC7736526 | biostudies-literature
Project description:BackgroundActivating transcription factor 3 (ATF3) is an early response gene that is activated in response to atherosclerotic stimulation and may be an important factor in inhibiting the progression of atherosclerosis. In this study, we directly measured the expression of ATF3 and inflammatory factors in human coronary atherosclerotic plaques to examine the relationship between ATF3 expression, inflammation and structural stability in human coronary atherosclerotic plaques.MethodsA total of 68 coronary artery specimens were collected from the autopsy group, including 36 cases of sudden death from coronary heart disease (SCD group) and 32 cases of acute death caused by mechanical injury with coronary atherosclerosis (CHD group). Twenty-two patients who had no coronary heart disease were collected as the control group (Con group). The histological structure of the coronary artery was observed under a light microscope after routine HE staining, and the intimal and lesion thicknesses, thickness of the fibrous cap, thickness of necrosis core, degree of lumen stenosis were assessed by image analysis software. Western blotting and immunohistochemistry were used to measure the expression and distribution of ATF3, inflammatory factors (CD45, IL-1β, TNF-α) and matrix metalloproteinase-9 (MMP-9) and vascular cell adhesion molecule 1 (VCAM1) in the coronary artery. The Pearson correlation coefficient was used to analyse the correlation between ATF3 protein expression and inflammatory factors and between ATF3 protein expression and structure-related indexes in the lesion group.ResultsCompared with those in the control group, the intima and necrotic core in the coronary artery were thickened, the fibrous cap became thin and the degree of vascular stenosis was increased in the lesion group, while the intima and necrotic core became thicker and the fibrous cap became thinner in the SCD group than in the CHD group (P < 0.05). There was no or low expression of ATF3, inflammatory factors, VCAM1 and MMP-9 in the control group, and the expression of inflammatory factors, VCAM1 and MMP-9 in the SCD group was higher than that in CHD group, while the expression of ATF3 in the SCD group was significantly lower than that in CHD group (P < 0.05). In the lesion group, the expression of ATF3 was negatively correlated with intimal and necrotic focus thickness, positively correlated with fibrous cap thickness (P < 0.01), and negatively correlated with inflammatory factors, VCAM1 and MMP-9 (P < 0.01).ConclusionsThe expression of ATF3 may be related to the progression and stability of atherosclerotic plaques, and may affect the structural stability of atherosclerotic plaques by regulating the inflammatory response, thus participating in the regulation of atherosclerotic progression.
| S-EPMC8317287 | biostudies-literature
Project description:ObjectiveHomozygosity for a 1.7 kb intragenic duplication of the Haptoglobin (Hp) gene (Hp 2-2 genotype), present in 36% of the population, has been associated with a 2-3 fold increased incidence of atherothrombosis in individuals with Diabetes (DM) in 10 longitudinal studies compared to DM individuals not homozygous for this duplication (Hp 1-1/2-1). The increased CVD risk associated with the Hp 2-2 genotype has been shown to be prevented with vitamin E supplementation in man. We sought to determine if there was an interaction between the Hp genotype and vitamin E on atherosclerotic plaque growth and stability in a transgenic model of the Hp polymorphism.Methods and resultsBrachiocephalic artery atherosclerotic plaque volume was serially assessed by high resolution ultrasound in 28 Hp 1-1 and 26 Hp 2-2 mice in a C57Bl/6 ApoE(-/-) background. Hp 2-2 mice had more rapid plaque growth and an increased incidence of plaque hemorrhage and rupture. Vitamin E significantly reduced plaque growth in Hp 2-2 but not in Hp 1-1 mice with a significant pharmacogenomic interaction between the Hp genotype and vitamin E on plaque growth.ConclusionsThese results may help explain why vitamin E supplementation in man can prevent CVD in Hp 2-2 DM but not in non Hp 2-2 DM individuals.
| S-EPMC4331216 | biostudies-literature
Project description:To elucidate the impact of Trem2 agonist on aortic gene expression during atherosclerosis.
2024-04-18 | GSE256189 | GEO
Project description:Atherosclerotic plaque rupture is the main cause of myocardial infarction and stroke. Both clinical and computational studies indicate that the shoulder region, where a plaque joins the vessel wall, is rupture-prone. Previous mechanistic studies focused on mechanical properties of the fibrous cap and tensile stresses, which could lead to tearing of the cap. Based on clinical observations of "mobile floating plaques," we postulate that de-adhesion between the fibrous cap and the underlying vessel wall may also play a role in plaque failure. Thus, measuring adhesive strength of the bond between plaque and vascular wall may provide useful new insights into plaque stability. Delamination experiments, widely used in examining inter-laminar adhesive strength of biological materials, were used to measure adhesive strength of advanced plaques in apolipoprotein E-knockout (apoE-KO) mice after 8 months on Western diet. We measured adhesive strength in terms of local energy release rate, G, during controlled plaque delamination. As a measure of the fracture energy required to delaminate a unit area of plaque from the underlying internal elastic lamina (IEL), G provides a quantitative measure of local adhesive strength of the plaque-IEL interface. The values for G acquired from 16 plaques from nine apoE-KO mouse aortas formed a positively skewed distribution with a mean of 24.5 J/m(2), median of 19.3 J/m(2), first quartile of 10.8 J/m(2), and third quartile of 34.1 J/m(2). These measurements are in the lower range of values reported for soft tissues. Histological studies confirmed delamination occurred at the interface between plaque and IEL.
| S-EPMC3156298 | biostudies-literature
Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies. 6 human carotid plaques were sectioned in 1 mm thick slices. Alternative slices were used for gene expression profiling in Affymetrix/Merck custom 1.0 arrays (GPL10687), or for immunohistochemistry studies (CD68, Actin)
2011-09-30 | E-GEOD-24495 | biostudies-arrayexpress
Project description:BackgroundLipoprotein(a) [Lp(a)] is associated with increased risk of myocardial infarction, although the mechanism for this observation remains uncertain.ObjectivesThis study aims to investigate whether Lp(a) is associated with adverse plaque progression.MethodsLp(a) was measured in patients with advanced stable coronary artery disease undergoing coronary computed tomography angiography at baseline and 12 months to assess progression of total, calcific, noncalcific, and low-attenuation plaque (necrotic core) in particular. High Lp(a) was defined as Lp(a) ≥ 70 mg/dL. The relationship of Lp(a) with plaque progression was assessed using linear regression analysis, adjusting for body mass index, segment involvement score, and ASSIGN score (a Scottish cardiovascular risk score comprised of age, sex, smoking, blood pressure, total and high-density lipoprotein [HDL]-cholesterol, diabetes, rheumatoid arthritis, and deprivation index).ResultsA total of 191 patients (65.9 ± 8.3 years of age; 152 [80%] male) were included in the analysis, with median Lp(a) values of 100 (range: 82 to 115) mg/dL and 10 (range: 5 to 24) mg/dL in the high and low Lp(a) groups, respectively. At baseline, there was no difference in coronary artery disease severity or plaque burden. Patients with high Lp(a) showed accelerated progression of low-attenuation plaque compared with low Lp(a) patients (26.2 ± 88.4 mm3 vs -0.7 ± 50.1 mm3; P = 0.020). Multivariable linear regression analysis confirmed the relation between Lp(a) and low-attenuation plaque volume progression (β = 10.5% increase for each 50 mg/dL Lp(a), 95% CI: 0.7%-20.3%). There was no difference in total, calcific, and noncalcific plaque volume progression.ConclusionsAmong patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core). This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis.
| S-EPMC8784819 | biostudies-literature
Project description:BackgroundVisfatin is a multifaceted protein that plays an important role in regulating a variety of physiological and pathological processes, including obesity, diabetes and cardiovascular disease. However, circulating visfatin levels in atherosclerosis plaque progression in patients with type 2 diabetes, or its association with the vascular territory affected remain unclear.MethodsWe evaluated the relationship between visfatin levels and carotid or femoral artery atherosclerosis in Chinese patients with type 2 diabetes. Serum levels of visfatin were measured by enzyme-linked immunosorbent assay (ELISA) in 97 inpatients with type 2 diabetes. Carotid and/or femoral atherosclerotic plaques were detected by B-mode ultrasound.ResultsSerum visfatin levels were elevated in the group with atherosclerotic plaques compared to the control group without plaques [0.68 (0.46-1.58) versus 0.45 (0.23-0.76) ng/mL, respectively, P = 0.0002]. Patients with carotid plaques showed higher visfatin levels than those with or without femoral plaques. Pearson's correlation analysis showed that serum visfatin levels were positively correlated with waist circumference (r = 0.226, P = 0.029), waist-hip ratio (r = 0.221, P = 0.032), TG (r = 0.222, P = 0.030) and number of plaques (r = 0.275, P = 0.009). Logistic regression analysis showed that a higher serum visfatin level was an independent predictor for the presence of atherosclerotic plaques.ConclusionsIn conclusion, among patients with T2DM, serum visfatin levels were elevated in those with atherosclerotic plaques, especially in patients with carotid atherosclerotic plaques. Serum visfatin may serve as a predictor of atherosclerotic plaques in patients with T2DM.
| S-EPMC6657107 | biostudies-literature
Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies.
2011-10-01 | GSE24495 | GEO
Project description:Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease.
| S-EPMC10266795 | biostudies-literature