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International Journal of Cardiology.... Aug 2024Longitudinal changes in gut microbiome and inflammation may be involved in the evolution of atherosclerosis after an acute coronary syndrome (ACS). We aimed to...
BACKGROUND
Longitudinal changes in gut microbiome and inflammation may be involved in the evolution of atherosclerosis after an acute coronary syndrome (ACS). We aimed to characterize repeated profiles of gut microbiota and peripheral CD4+ T lymphocytes during the first year after an ACS, and to address their relationship with atherosclerotic plaque changes.
METHODS
Over one year we measured the microbiome, peripheral counts of CD4+ T populations and cytokines in 67 patients shortly after a first ACS. We compared baseline measurements to those of a matched population of 40 chronic patients. A subgroup of 20 ACS patients underwent repeated assessment of fibrous cap thickness (FCT) of a non-culprit lesion.
RESULTS
At admission, ACS patients showed gut dysbiosis compared with the chronic group, which was rapidly reduced and remained low at 1-year. Also, their Th1 and Th2 CD4+ T counts were increased but decreased over time. The CD4+ T counts were related to ongoing changes in gut microbiome. Unsupervised clustering of repeated CD4+ Th0, Th1, Th2, Th17 and Treg counts in ACS patients identified two different cell trajectory patterns, related to cytokines. The group of patients following a high-CD4+ T cell trajectory showed a one-year reduction in their FCT [net effect = -24.2 µm; p = 0.016].
CONCLUSIONS
Patients suffering an ACS show altered profiles of microbiome and systemic inflammation that tend to mimic values of chronic patients after 1-year. However, in one-third of patients, this inflammatory state remains particularly dysregulated. This persistent inflammation is likely related to plaque vulnerability as evident by fibrous cap thinning (Clinical Trial NCT03434483).
PubMed: 38912228
DOI: 10.1016/j.ijcha.2024.101438 -
Journal of Advanced Research Jun 2024Atherosclerosis, traditionally considered a lipid-related disease, is now understood as a chronic inflammatory condition with significant global health implications. (Review)
Review
INTRODUCTION
Atherosclerosis, traditionally considered a lipid-related disease, is now understood as a chronic inflammatory condition with significant global health implications.
OBJECTIVES
This review aims to delve into the complex interactions among immune cells, cytokines, and the inflammatory cascade in atherosclerosis, shedding light on how these elements influence both the initiation and progression of the disease.
METHODS
This review draws on recent clinical research to elucidate the roles of key immune cells, macrophages, T cells, endothelial cells, and clonal hematopoiesis in atherosclerosis development. It focuses on how these cells and process contribute to disease initiation and progression, particularly through inflammation-driven processes that lead to plaque formation and stabilization. Macrophages ingest oxidized low-density lipoprotein (oxLDL), which partially converts to high-density lipoprotein (HDL) or accumulates as lipid droplets, forming foam cells crucial for plaque stability. Additionally, macrophages exhibit diverse phenotypes within plaques, with pro-inflammatory types predominating and others specializing in debris clearance at rupture sites. The involvement of CD4 T and CD8 T cells in these processes promotes inflammatory macrophage states, suppresses vascular smooth muscle cell proliferation, and enhances plaque instability.
RESULTS
The nuanced roles of macrophages, T cells, and the related immune cells within the atherosclerotic microenvironment are explored, revealing insights into the cellular and molecular pathways that fuel inflammation. This review also addresses recent advancements in imaging and biomarker technology that enhance our understanding of disease progression. Moreover, it points out the limitations of current treatment and highlights the potential of emerging anti-inflammatory strategies, including clinical trials for agents such as p38MAPK, tumor necrosis factor α (TNF-α), and IL-1β, their preliminary outcomes, and the promising effects of canakinumab, colchicine, and IL-6R antagonists.
CONCLUSION
This review explores cutting-edge anti-inflammatory interventions, their potential efficacy in preventing and alleviating atherosclerosis, and the role of nanotechnology in delivering drugs more effectively and safely.
PubMed: 38909884
DOI: 10.1016/j.jare.2024.06.016 -
EBioMedicine Jun 2024Mapping gut microecological features to serum metabolites (SMs) will help identify functional links between gut microbiome and cardiometabolic health.
BACKGROUND
Mapping gut microecological features to serum metabolites (SMs) will help identify functional links between gut microbiome and cardiometabolic health.
METHODS
This study encompassed 836-1021 adults over 9.7 year in a cohort, assessing metabolic syndrome (MS), carotid atherosclerotic plaque (CAP), and other metadata triennially. We analyzed mid-term microbial metagenomics, targeted fecal and serum metabolomics, host genetics, and serum proteomics.
FINDINGS
Gut microbiota and metabolites (GMM) accounted for 15.1% overall variance in 168 SMs, with individual GMM factors explaining 5.65%-10.1%, host genetics 3.23%, and sociodemographic factors 5.95%. Specifically, GMM elucidated 5.5%-49.6% variance in the top 32 GMM-explained SMs. Each 20% increase in the 32 metabolite score (derived from the 32 SMs) correlated with 73% (95% confidence interval [CI]: 53%-95%) and 19% (95% CI: 11%-27%) increases in MS and CAP incidences, respectively. Among the 32 GMM-explained SMs, sebacic acid, indoleacetic acid, and eicosapentaenoic acid were linked to MS or CAP incidence. Serum proteomics revealed certain proteins, particularly the apolipoprotein family, mediated the relationship between GMM-SMs and cardiometabolic risks.
INTERPRETATION
This study reveals the significant influence of GMM on SM profiles and illustrates the intricate connections between GMM-explained SMs, serum proteins, and the incidence of MS and CAP, providing insights into the roles of gut dysbiosis in cardiometabolic health via regulating blood metabolites.
FUNDING
This study was jointly supported by the National Natural Science Foundation of China, Key Research and Development Program of Guangzhou, 5010 Program for Clinical Research of Sun Yat-sen University, and the 'Pioneer' and 'Leading goose' R&D Program of Zhejiang.
PubMed: 38908099
DOI: 10.1016/j.ebiom.2024.105209 -
International Journal of Biological... 2024Shear stress-induced Dickkopf-1 (DKK1) secretion by endothelial cells (ECs) promotes EC dysfunction and accelerates atherosclerosis (AS). However, the paracrine role of...
Shear stress-induced Dickkopf-1 (DKK1) secretion by endothelial cells (ECs) promotes EC dysfunction and accelerates atherosclerosis (AS). However, the paracrine role of endothelial DKK1 in modulating adjacent smooth muscle cells (SMCs) in atherosclerosis remains unclear. This study investigated the role of EC-secreted DKK1 in SMC-derived foam cell formation under shear stress, and . Parallel-plate co-culture flow system was used to explore the cellular communication between ECs and SMCs under shear stress . Endothelium-specific knockout of DKK1 (DKK1/APOE) and endothelium-specific overexpression of DKK1 (DKK1) mice were constructed to investigate the role of endothelial DKK1 in atherosclerosis and SMC-derived foam cell formation . RNA sequencing (RNA-seq) was used to identify the downstream targets of DKK1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot, coimmunoprecipitation (Co-IP) assays and chromatin immunoprecipitation (ChIP) experiments were conducted to explore the underlying regulatory mechanisms. DKK1 is transcriptionally upregulated in ECs under conditions of low shear stress, but not in co-cultured SMCs. However, DKK1 protein in co-cultured SMCs is increased via uptake of low shear stress-induced endothelial DKK1, thereby promoting lipid uptake and foam cell formation in co-cultured SMCs via the post-translational upregulation of scavenger receptor-A (SR-A) verified in parallel-plate co-culture flow system, DKK1 and DKK1 mice. RNA sequencing revealed that DKK1-induced SR-A upregulation in SMCs is dependent on Ubiquitin-specific Protease 53 (USP53), which bound to SR-A via its USP domain and cysteine at position 41, exerting deubiquitination to maintain the stability of the SR-A protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby mediating the effect of DKK1 on lipid uptake in SMCs. Moreover, DKK1 regulates the transcription of USP53 by facilitating the binding of transcription factor CREB to the USP53 promoter. SMC-specific overexpression of USP53 via adeno-associated virus serotype 2 vectors in DKK1/APOE mice reversed the alleviation of atherosclerotic plaque burden, SR-A expression and lipid accumulation in SMCs within plaques resulting from DKK1 deficiency. Our findings demonstrate that, endothelial DKK1, induced by pathological low shear stress, acts as an intercellular mediator, promoted the foam cell formation of SMCs. These results suggest that targeted intervention with endothelial DKK1 may confer beneficial effects on atherosclerosis.
Topics: Animals; Atherosclerosis; Mice; Intercellular Signaling Peptides and Proteins; Foam Cells; Myocytes, Smooth Muscle; Endothelial Cells; Humans; Ubiquitination; Male; Coculture Techniques; Mice, Knockout; Ubiquitin-Specific Proteases; Mice, Inbred C57BL
PubMed: 38904030
DOI: 10.7150/ijbs.91957 -
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