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Journal of the American College of... Jun 2024Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk...
BACKGROUND
Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk factors remain unclear.
OBJECTIVES
This study sought to determine whether autoimmune diseases independently correlate with coronary atherosclerosis and ASCVD risk and whether traditional cardiovascular risk factors modulate the risk.
METHODS
The study included 85,512 patients from the Western Denmark Heart Registry undergoing coronary computed tomography angiography. A diagnosis of 1 of 18 autoimmune diseases was assessed. Adjusted OR (aOR) for any plaque, any coronary artery calcification (CAC), CAC of >90th percentile, and obstructive coronary artery disease as well as adjusted HR (aHR) for ASCVD were calculated.
RESULTS
During 5.3 years (Q1-Q3: 2.8-8.2 years) of follow-up, 3,832 ASCVD events occurred. A total of 4,064 patients had a diagnosis of autoimmune disease, which was associated with both presence of any plaque (aOR: 1.29; 95% CI: 1.20-1.40), any CAC (aOR: 1.28; 95% CI: 1.19-1.37), and severe CAC of >90th percentile (aOR: 1.53; 95% CI: 1.39-1.68), but not with having obstructive coronary artery disease (aOR: 1.04; 95% CI: 0.91-1.17). Patients with autoimmune diseases had a 46% higher risk (aHR: 1.46; 95% CI: 1.29-1.65) for ASCVD. Traditional cardiovascular risk factors were strongly associated with future ASCVD events, and a favorable cardiovascular risk factor profile in autoimmune patients was associated with ∼54% lower risk compared to patients with presence of risk factors (aHR: 0.46; 95% CI: 0.27-0.81).
CONCLUSIONS
Autoimmune diseases were independently associated with higher burden of coronary atherosclerosis and higher risk for future ASCVD events, with risk accentuated by traditional cardiovascular risk factors. These findings suggest that autoimmune diseases increase risk through accelerated atherogenesis and that cardiovascular risk factor control is key for improving prognosis in patients with autoimmune diseases.
Topics: Humans; Coronary Artery Disease; Male; Female; Autoimmune Diseases; Middle Aged; Aged; Denmark; Severity of Illness Index; Registries; Computed Tomography Angiography; Coronary Angiography; Risk Factors; Myocardial Ischemia; Follow-Up Studies
PubMed: 38897674
DOI: 10.1016/j.jacc.2024.04.030 -
Biochemical and Biophysical Research... Jun 2024Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells...
BACKGROUND
Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis.
METHODS
We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis.
RESULTS
Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK.
CONCLUSION
Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis.
PubMed: 38897039
DOI: 10.1016/j.bbrc.2024.150236 -
Inflammation Research : Official... Jun 2024Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this...
BACKGROUND
Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this process also leads to programmed death of macrophages. So far, the role of macrophage death in the progression of atherosclerosis remains controversial. Also, the underlying mechanism by which transcriptional regulation and reprogramming triggered by macrophage death pathways lead to changes in vascular inflammation and remodeling are still largely unknown. TRIM25-mediated RIG-I signaling plays a key role in regulation of macrophages fate, however the role of TRIM25 in macrophage death-mediated atherosclerotic progression remains unclear. This study aims to investigate the relationship between TRIM25 and macrophage death in atherosclerosis.
METHODS
A total of 34 blood samples of patients with coronary stent implantation, including chronic total occlusion (CTO) leisions (n = 14) or with more than 50% stenosis of a coronary artery but without CTO leisions (n = 20), were collected, and the serum level of TRIM25 was detected by ELISA. Apoe mice with or without TRIM25 gene deletion were fed with the high-fat diet (HFD) for 12 weeks and the plaque areas, necrotic core size, aortic fibrosis and inflammation were investigated. TRIM25 wild-type and deficient macrophages were isolated, cultured and stimulated with ox-LDL, RNA-seq, real-time PCR, western blot and FACS experiments were used to screen and validate signaling pathways caused by TRIM25 deletion.
RESULTS
Downregulation of TRIM25 was observed in circulating blood of CTO patients and also in HFD-induced mouse aortas. After HFD for 12 weeks, TRIM25ApoeE mice developed smaller atherosclerotic plaques, less inflammation, lower collagen content and aortic fibrosis compared with TRIM25ApoeE mice. By RNA-seq and KEGG enrichment analysis, we revealed that deletion of TRIM25 mainly affected pyroptosis and necroptosis pathways in ox-LDL-induced macrophages, and the expressions of PARP1 and RIPK3, were significantly decreased in TRIM25 deficient macrophages. Overexpression of TRIM25 promoted M1 polarization and necroptosis of macrophages, while inhibition of PARP1 reversed this process. Further, we observed that XRCC1, a repairer of DNA damage, was significantly upregulated in TRIM25 deficient macrophages, inhibiting PARP1 activity and PARP1-mediated pro-inflammatory change, M1 polarization and necroptosis of macrophages. By contrast, TRIM25 overexpression mediated ubiquitination of XRCC1, and the inhibition of XRCC1 released PARP1, and activated macrophage M1 polarization and necroptosis, which accelerated aortic inflammation and atherosclerotic plaque progression.
CONCLUSIONS
Our study has uncovered a crucial role of the TRIM25-XRCC1-PARP1-RIPK3 axis in regulating macrophage death during atherosclerosis, and we highlight the potential therapeutic significance of macrophage reprogramming regulation in preventing the development of atherosclerosis.
PubMed: 38896288
DOI: 10.1007/s00011-024-01906-4 -
Frontiers in Medicine 2024[This corrects the article DOI: 10.3389/fmed.2024.1284199.].
[This corrects the article DOI: 10.3389/fmed.2024.1284199.].
PubMed: 38895189
DOI: 10.3389/fmed.2024.1416622 -
Diagnostics (Basel, Switzerland) May 2024The aim of the study was to assess the relationship between the presence of atherosclerotic lesions in the carotid arteries detected by ultrasound and the occurrence of...
The aim of the study was to assess the relationship between the presence of atherosclerotic lesions in the carotid arteries detected by ultrasound and the occurrence of atherosclerosis in the coronary arteries determined by computed tomography (CT) in patients with arterial hypertension (HTA). A total of 83 patients with HTA were qualified for the study (age: 71.3 ± 8.5 years). All subjects underwent carotid arteries ultrasound and coronary arteries CT. The carotid plaque score was assessed using ultrasound. The studied group was divided into two subgroups: a subgroup with the carotid plaque score ≤ 1 (A) and a subgroup with carotid plaque score ≥2 (B). Coronary arteries CT assessed coronary artery calcium score (CACS) and degree of coronary stenosis based on CAD-RADS. In subgroup B, a significantly higher CACS (411.3 ± 70.1 vs. 93.5 ± 31.8) and significantly higher grade in the CAD-RADS classification were demonstrated than in subgroup A (CAD-RADS ≥ 3: 21.8 vs. 6.0%). The regression analysis showed that carotid plaque score and age are independent risk factors for the severity of atherosclerotic lesions in the coronary arteries. In summary, ultrasound assessment of the carotid plaque score in patients with HTA could be considered as surrogate indicator of the risk and severity of atherosclerotic changes in the coronary arteries, but further studies are necessary to corroborate these results.
PubMed: 38893628
DOI: 10.3390/diagnostics14111101 -
Diagnostics (Basel, Switzerland) May 2024Atherosclerotic plaque buildup in the coronary and carotid arteries is pivotal in the onset of acute myocardial infarctions or cerebrovascular events, leading to... (Review)
Review
Atherosclerotic plaque buildup in the coronary and carotid arteries is pivotal in the onset of acute myocardial infarctions or cerebrovascular events, leading to heightened levels of illness and death. Atherosclerosis is a complex and multistep disease, beginning with the deposition of low-density lipoproteins in the arterial intima and culminating in plaque rupture. Modern technology favors non-invasive imaging techniques to assess atherosclerotic plaque and offer insights beyond mere artery stenosis. Among these, computed tomography stands out for its widespread clinical adoption and is prized for its speed and accessibility. Nonetheless, some limitations persist. The introduction of photon-counting computed tomography (PCCT), with its multi-energy capabilities, enhanced spatial resolution, and superior soft tissue contrast with minimal electronic noise, brings significant advantages to carotid and coronary artery imaging, enabling a more comprehensive examination of atherosclerotic plaque composition. This narrative review aims to provide a comprehensive overview of the main concepts related to PCCT. Additionally, we aim to explore the existing literature on the clinical application of PCCT in assessing atherosclerotic plaque. Finally, we will examine the advantages and limitations of this recently introduced technology.
PubMed: 38893593
DOI: 10.3390/diagnostics14111065 -
Journal of Clinical Medicine May 2024Atherosclerosis is the predominant underlying etiopathology of coronary artery disease. Changes in plaque phenotype from stable to high risk may spur future major... (Review)
Review
Atherosclerosis is the predominant underlying etiopathology of coronary artery disease. Changes in plaque phenotype from stable to high risk may spur future major adverse cardiac events (MACE). Different pharmacological therapies have been implemented to mitigate this risk. Over the last two decades, intravascular imaging modalities have emerged in clinical studies to clarify how these therapies may affect the composition and burden of coronary plaques. Lipid-lowering agents, such as statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, were shown not only to reduce low-density lipoprotein levels and MACE but also to directly affect features of coronary plaque vulnerability. Studies have demonstrated that lipid-lowering therapy reduces the percentage of atheroma volume and number of macrophages and increases fibrous cap thickness. Future studies should answer the question of whether pharmacological plaque stabilization may be sufficient to mitigate the risk of MACE for selected groups of patients with atherosclerotic coronary disease.
PubMed: 38892807
DOI: 10.3390/jcm13113096 -
International Journal of Molecular... May 2024Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered... (Review)
Review
Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered increasing recognition, with recent studies revealing its prevalence to be approximately 40% among ACS patients, challenging earlier assumptions based on autopsy data. Notably, PE exhibits distinct epidemiological features, preferentially affecting younger demographics, particularly women, and often manifesting as a non-ST-segment elevation myocardial infarction. There are seasonal variations, with PE events being less common in winter, potentially linked to physiological changes and cholesterol solidification, while peaking in summer, warranting further investigation. Moving to molecular mechanisms, PE presents a unique profile characterized by a lesser degree of inflammation compared to PR, with endothelial shear stress emerging as a plausible molecular mechanism. Neutrophil activation, toll-like receptor-2 pathways, and hyaluronidase 2 expression are among the factors implicated in PE pathophysiology, underscoring its multifactorial nature. Advancements in intravascular imaging diagnostics, particularly optical coherence tomography and near-infrared spectroscopy coupled with intravascular ultrasound, offer unprecedented insights into plaque composition and morphology. Artificial intelligence algorithms show promise in enhancing diagnostic accuracy and streamlining image interpretation, augmenting clinician decision-making. Therapeutically, the management of PE evolves, with studies exploring less invasive approaches such as antithrombotic therapy without stenting, particularly in cases identified early through intravascular imaging. Additionally, the potential role of drug-coated balloons in reducing thrombus burden and minimizing future major adverse cardiovascular events warrants further investigation. Looking ahead, the integration of advanced imaging modalities, biomarkers, and artificial intelligence promises to revolutionize the diagnosis and treatment of coronary PE, ushering in a new era of personalized and precise cardiovascular care.
Topics: Humans; Plaque, Atherosclerotic; Tomography, Optical Coherence; Coronary Artery Disease; Acute Coronary Syndrome
PubMed: 38891972
DOI: 10.3390/ijms25115786 -
Nutrition, Metabolism, and... May 2024Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the...
BACKGROUND AND AIMS
Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the vascular endothelium has been hypothesized to be an initial step in the formation of atherosclerotic plaques, with inflammatory cytokines serving as the signaling mechanism for concomitant macrophage activation. Supplementation with the antioxidative macular xanthophylls (lutein [L], zeaxanthin [Z], and meso-zeaxanthin [MZ]) has been shown to aid in the reduction of inflammatory physiologic responses; therefore, we hypothesized that in our study population, supplementation with these xanthophylls would facilitate a systemic reduction in markers of inflammation and cardiovascular lipid oxidation.
METHODS AND RESULTS
In this double-blind placebo-controlled supplementation study, participants were randomly allocated to receive the active intervention containing L (10 mg) + MZ (10 mg) + Z (2 mg) or placebo (containing sunflower oil). Serum concentrations of carotenoids (assessed by HPLC), inflammatory cytokines (IL-6, IL-1β, TNF-α) and oxidized LDL (OxLDL; by solid-phase sandwich ELISA) were measured at baseline and at 6-months. Results showed that over the supplementation period, compared to placebo, the active group demonstrated statistically significant increases in serum concentrations of L, Z, & MZ (p < 0.05), reductions in inflammatory cytokines IL-1β (p < 0.001) and TNF-α (p = 0.003), as well as a corresponding reduction in serum OxLDL (p = 0.009).
CONCLUSIONS
Our data show that L, Z, & MZ supplementation results in decreased serum IL-1β, TNF-α, and OxLDL. This suggests that these carotenoids are acting systemically to attenuate oxidative lipid products and inflammation, thus reducing their contribution to atherosclerotic plaque formation.
PubMed: 38890092
DOI: 10.1016/j.numecd.2024.05.009 -
Circulation. Cardiovascular Imaging Jun 2024This study aimed to develop and validate a computed tomography angiography based machine learning model that uses plaque composition data and degree of carotid stenosis...
BACKGROUND
This study aimed to develop and validate a computed tomography angiography based machine learning model that uses plaque composition data and degree of carotid stenosis to detect symptomatic carotid plaques in patients with carotid atherosclerosis.
METHODS
The machine learning based model was trained using degree of stenosis and the volumes of 13 computed tomography angiography derived intracarotid plaque subcomponents (eg, lipid, intraplaque hemorrhage, calcium) to identify plaques associated with cerebrovascular events. The model was internally validated through repeated 10-fold cross-validation and tested on a dedicated testing cohort according to discrimination and calibration.
RESULTS
This retrospective, single-center study evaluated computed tomography angiography scans of 268 patients with both symptomatic and asymptomatic carotid atherosclerosis (163 for the derivation set and 106 for the testing set) performed between March 2013 and October 2019. The area-under-receiver-operating characteristics curve by machine learning on the testing cohort (0.89) was significantly higher than the areas under the curve of traditional logit analysis based on the degree of stenosis (0.51, <0.001), presence of intraplaque hemorrhage (0.69, <0.001), and plaque composition (0.78, <0.001), respectively. Comparable performance was obtained on internal validation. The identified plaque components and associated cutoff values that were significantly associated with a higher likelihood of symptomatic status after adjustment were the ratio of intraplaque hemorrhage to lipid volume (≥50%, 38.5 [10.1-205.1]; odds ratio, 95% CI) and percentage of intraplaque hemorrhage volume (≥10%, 18.5 [5.7-69.4]; odds ratio, 95% CI).
CONCLUSIONS
This study presented an interpretable machine learning model that accurately identifies symptomatic carotid plaques using computed tomography angiography derived plaque composition features, aiding clinical decision-making.
Topics: Humans; Computed Tomography Angiography; Male; Machine Learning; Female; Retrospective Studies; Plaque, Atherosclerotic; Aged; Middle Aged; Carotid Artery Diseases; Carotid Stenosis; Predictive Value of Tests; Reproducibility of Results; Carotid Arteries; Severity of Illness Index
PubMed: 38889214
DOI: 10.1161/CIRCIMAGING.123.016274