Atherosclerosis最新文献

Aim

We aimed at creating and validating a prognostic model incorporating easily accessible clinical and laboratory parameters to forecast the likelihood of short-term progression of carotid atherosclerosis.

Methods

A prediction model was developed and validated for carotid plaque progression within 2 years in an early middle-age population in China. Progression was defined as the new appearance of carotid plaque or stenosis among participants who had normal carotid status at baseline. Leveraging data from a health check-up chain, predictors were identified using statistical methods including stepwise logistic regression, Markov Chain Monte Carlo (MCMC) simulation, random forest analysis and least absolute shrinkage selection operator (Lasso). Model performance was assessed. Bootstrap internal validation, validation on another check-up population and subgroup analysis were also conducted.

Results

Among 7765 participants, predictors including age, diastolic blood pressure, uric acid levels, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were identified for carotid plaque progression in 2 years. The developed prediction model demonstrated good discrimination (AUC = 0.755, 95%CI:0.736–0.774) and calibration ability (slope = 0.922 and interception = 0.007) among development data, as well as among validation data (AUC = 0.759, 95%CI:0.674–0.770; slope = 1.076 and intercept = −0.014). Internal validation using bootstrap method yielded an adjusted AUC of 0.753. The model's performance remained consistent across different subgroups.

Conclusions

Our study presents a validated risk prediction model for carotid plaque progression in an early middle age population, offering a valuable tool for early identification and monitoring of cardiovascular risks. The model's robustness and applicability across different subgroups highlight its potential utility in preemptive cerebrovascular and cardiovascular disease management.

Background and aims

The potential impact of peripheral artery disease (PAD) on kidney outcomes is not well understood. The aim of this study was to explore the association between PAD and end-stage kidney disease (ESKD) and chronic kidney disease (CKD).

Methods

Among 14,051 participants (mean age 54 [SD 6 years]) from the Atherosclerosis Risk in Communities study, we categorized PAD status as symptomatic PAD (intermittent claudication or leg revascularization), asymptomatic PAD (ankle-brachial index [ABI] ≤0.90 without clinical history of symptoms), and ABI 0.91–1.00, 1.01–1.10, 1.11–1.20 (reference), 1.21–1.30, and >1.30. We evaluated their associations with two kidney outcomes: ESKD (the need of renal replacement therapy or death due to kidney disease) and CKD (ESKD cases or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² with a ≥25 % decline from the baseline) using multivariable Cox proportional hazards models.

Results

Over ∼30 years of follow-up, there were 598 cases of incident ESKD and 4686 cases of incident CKD. After adjusting for potential confounders, both symptomatic PAD and asymptomatic PAD conferred a significantly elevated risk of ESKD (hazard ratio 2.28 [95 % confidence interval 1.23–4.22] and 1.75 [1.19–2.57], respectively). Corresponding estimates for CKD were 1.54 (1.14–2.09) and 1.63 (1.38–1.93). Borderline low ABI 0.91–1.00 also showed elevated risk of adverse kidney outcomes after adjustment for demographic variables. Largely consistent results were observed across demographic and clinical subgroups. Conclusions: Symptomatic PAD and asymptomatic PAD were independently associated with an elevated risk of ESKD and CKD. These results highlight the importance of monitoring kidney function in persons with PAD, even when symptoms are absent.

The subendothelial retention of circulating lipoproteins on extracellular matrix proteins and proteoglycans is one of the earliest events in the development of atherosclerosis. Multiple factors, including the size, type, composition, surrounding pH, and chemical modifications to lipoproteins, influence the electrostatic interactions between relevant moieties of the apolipoproteins on lipoproteins and the glycosaminoglycans of proteoglycans. The length and chemical composition of glycosaminoglycan chains attached to proteoglycan core proteins determine the extent of initial lipoprotein binding and retention in the artery wall. The phenomena of hyperelongation of glycosaminoglycan chains is associated with initial lipid retention and later atherosclerotic plaque formation. This review includes a summary of the current literature surrounding cellular mechanisms leading to GAG chain modification and lipid retention and discusses potential therapeutic strategies to target lipoprotein:proteoglycan interactions to prevent the development and progression of atherosclerosis.

Background and aims

Tobacco smoking is a known risk factor for atherosclerotic disease, with more elevated risks in women compared to men. We hypothesized that atherosclerotic plaques from smokers show different gene expression patterns compared to non-smokers, in a sex-specific manner.

Methods

Gene expression data of 625 carotid plaques (151 females and 474 males) were analyzed for differential gene expression between current smokers (n = 226) and non-smokers (n = 399). All analyses were stratified by sex and by molecular plaque characteristics. Finally, we projected the activity of gene regulatory networks and utilized single-cell transcriptomics from 38 plaques (26 males and 12 females) to interpret the sex- and plaque-type specific signals.

Results

We observed higher expression levels of CRLF1 gene in atherosclerotic plaques from smokers compared to non-smokers (log2FC = 0.48, FDR = 0.012). CRLF1 upregulation was interacting with sex (p = 0.01) and was more pronounced in females (log2FC = 0.93, p = 1.53E-05) compared to males (log2FC = 0.35, p = 0.0018). Through single-cell RNA-seq analysis, we identified the highest CRLF1 expression within the transitioning and synthetic smooth muscle cell populations. CRLF1 expression was increased in fibro-inflammatory and fibro-cellular plaque types. Gene annotations pointed to increased expression of CRLF1 in networks with extracellular matrix related genes.

Conclusions

Atherosclerotic plaques from current smokers show sex-dependent upregulation of smooth muscle cell gene CRLF1. This may explain the different contributions of smoking to cardiovascular risk in females.

Background and aims

Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear.

Methods

The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe^−/−) and Apoe^−/− DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe^−/− mice to explore the effects on atherosclerosis.

Results

DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe^−/− mice.

Conclusions

Our data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.

Background and aims

Lipids constitute one of the main components of atherosclerosis lesions and are the mediators of many mechanisms involved in plaque progression and stability. Here we tested the hypothesis that lipids known to be involved in plaque development exhibited associations with plaque vulnerability. We used spatial lipidomics to overcome plaque heterogeneity and to compare lipids from specific regions of symptomatic and asymptomatic human carotid atherosclerotic plaques.

Methods

Carotid atherosclerotic plaques were collected from symptomatic and asymptomatic patients. Plaque lipids were analyzed with the spatial lipidomics technique matrix-assisted laser desorption/ionization mass spectrometry imaging, and histology and immunofluorescence were used to segment the plaques into histomolecularly distinct regions.

Results

Macrophage-rich regions from symptomatic lesions were found to be enriched in phosphatidylcholines (synthesized to counteract excess free cholesterol), while the same region from asymptomatic plaques were enriched in polyunsaturated cholesteryl esters and triglycerides, characteristic of functional lipid droplets. Vascular smooth muscle cells (VSMCs) of the fibrous cap of asymptomatic plaques were enriched in lysophosphatidylcholines and cholesteryl esters, know to promote VSMC proliferation and migration, crucial for the buildup of the fibrous cap stabilizing the plaque.

Conclusions

The investigation of the region-specific lipid composition of symptomatic and asymptomatic human atherosclerotic plaques revealed specific lipid markers of plaque outcome, which could be linked to known biological characteristics of stable plaques.

Background and aims

Long-term fasting (LF) is increasingly emerging as a non-pharmacological approach to modulate risk factors associated with the development of atherosclerotic cardiovascular diseases (ASCVD). However, protection from ASCVD is more tied to the functionality of high-density lipoprotein (HDL) than its plasma levels. Our prospective interventional study focuses on the functional properties of lipoproteins in modulating cholesterol homeostasis on peripheral cells and examines how LF may influence this and lipoprotein subclass composition. For that purpose, we investigated its impact on HDL-cholesterol efflux capacity (CEC), and on serum cholesterol loading capacity (CLC).

Methods

Forty healthy subjects (50 % females) underwent medically supervised 9-day fasting (250 kcal/day) in a specialised facility. Thirty-two subjects had a follow-up examination after one month of food reintroduction.

Results

LF was well tolerated and increased self-reported energy levels. Fasting reduced triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and HDL cholesterol (HDL-C). Very-low-density lipoprotein cholesterol (VLDL-C) and LDL3-C showed sustained reductions at follow-up. Only HDL-C, specifically HDL2-C levels, increased at follow-up. Total HDL-CEC decreased during LF and increased above baseline at follow-up. Fasting decreased ATP binding cassette (ABC)A1-mediated HDL-CEC whereas ABCG1-mediated HDL-CEC remained unaffected. Aqueous diffusion increased at follow up. LF decreased serum CLC and then returned to baseline levels.

Conclusions

LF not only maintains lipoprotein functionality but also contributes to a favorable shift in the atherogenic risk profile, which persists even after food reintroduction. This further emphasizes the importance of considering HDL functionality alongside traditional lipid measurements to understand the potential for non-pharmacological interventions like LF to promote cardiovascular prevention and health.

Trial registration number

NCT05031598.

Background and aims

The objective of this study was to investigate the efficacy of CRISPR/Cas9-mediated A4GALT suppression in rescuing endothelial dysfunction in Fabry disease (FD) endothelial cells (FD-ECs) derived from human induced pluripotent stem cells (hiPSCs).

Methods

We differentiated hiPSCs (WT (wild-type), WTC-11), GLA-mutant hiPSCs (GLA-KO, CMC-Fb-002), and CRISPR/Cas9-mediated A4GALT-KO hiPSCs (GLA/A4GALT-KO, Fb-002-A4GALT-KO) into ECs and compared FD phenotypes and endothelial dysfunction. We also analyzed the effect of A4GALT suppression on reactive oxygen species (ROS) formation and transcriptome profiles through RNA sequencing.

Results

GLA-mutant hiPSC-ECs (GLA-KO and CMC-Fb-002) showed downregulated expression of EC markers and significantly reduced α-GalA expression with increased Gb-3 deposition and intra-lysosomal inclusion bodies. However, CRISPR/Cas9-mediated A4GALT suppression in GLA/A4GALT-KO and Fb-002-A4GALT-KO hiPSC-ECs increased expression levels of EC markers and rescued these FD phenotypes. GLA-mutant hiPSC-ECs failed to form tube-like structure in tube formation assays, showing significantly decreased migration of cells into the scratched wound area. In contrast, A4GALT suppression improved tube formation and cell migration capacity. Western blot analysis revealed that MAPK and AKT phosphorylation levels were downregulated while SOD and catalase were upregulated in GLA-KO hiPSC-ECs. However, suppression of A4GALT restored these protein alterations. RNA sequencing analysis demonstrated significant transcriptome changes in GLA-mutant EC, especially in angiogenesis, cell death, and cellular response to oxidative stress. However, these were effectively restored in GLA/A4GALT-KO hiPSC-ECs.

Conclusions

CRISPR/Cas9-mediated A4GALT suppression rescued FD phenotype and endothelial dysfunction in GLA-mutant hiPSC-ECs, presenting a potential therapeutic approach for FD-vasculopathy.