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Journal of the American Heart... Jun 2024Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins...
Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.
BACKGROUND
Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans.
METHODS AND RESULTS
Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA- rats. This competitive reduction was dose dependent (25-250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA rats.
CONCLUSIONS
Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.
PubMed: 38934863
DOI: 10.1161/JAHA.123.032419 -
Medical Principles and Practice :... Jun 2024Despite all advances in treatment, no-reflow, large thrombus burden (LTB), and myocardial blush grade (MBG) are associated with adverse cardiovascular outcomes in...
Aortic Arch Calcification in Predicting Unfavorable Angiographic Outcomes for Patients With ST-Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.
BACKGROUND
Despite all advances in treatment, no-reflow, large thrombus burden (LTB), and myocardial blush grade (MBG) are associated with adverse cardiovascular outcomes in ST-elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). Aortic arch calcification (AAC) is associated with subclinical atherosclerosis and adverse cardiovascular events. We aimed to examine the relationship between AAC and unfavorable angiographic outcomes such as no-reflow, MBG, and LTB in STEMI patients undergoing PCI.
METHODS
A total of 269 consecutive patients who presented with STEMI and underwent primary PCI were included in the study prospectively. Patients were divided into 3 groups according to AAC degree: Grade 0, Grade 1, and Grade 2/3. Unfavorable angiographic results; They were divided into 2 groups according to whether there was no-reflow, 2 groups as LTB and small TB according to thrombus burden, and 4 groups according to MBG between 0-3.
RESULTS
LTB, no-reflow, and MBG 0/1 were significantly higher in the Grade 2/3 AAC group compared to the Grade 0 and Grade 1 groups (all p<0.05). Moreover, Grade2/3 AAC was found to be an independent predictor for LTB, MBG 0/1, and no-reflow (OR = 2.480; 95% CI: 1.398-4.400; p = 0.002, OR = 2.364; 95% CI: 1.296-4.321, p = 0.005, OR= 4.170; 95% CI: 1.671-9.100, p=0.004, respectively). Patients were then classified according to thrombus burden, MBG, and no-reflow status. Grade 2/3 AAC was significantly higher than Grade 0/1 AAC in the LTB, MBG 0/1, and no-reflow groups (all p<0.05).
CONCLUSION
AAC can be used as a reliable indicator in predicting no-reflow, MBG 0/1, and LTB in STEMI patients undergoing primary PCI.
PubMed: 38934156
DOI: 10.1159/000540026 -
Heliyon Jun 2024Neutrophils play important roles in atherosclerosis and atherothrombosis. Bactericidal/permeability-increasing protein (BPI) is mainly expressed in the granules of human...
BACKGROUND
Neutrophils play important roles in atherosclerosis and atherothrombosis. Bactericidal/permeability-increasing protein (BPI) is mainly expressed in the granules of human neutrophils in response to inflammatory stress. This observational, cross-sectional study investigated the plasma level of BPI in patients with acute coronary syndrome (ACS) and its correlation with blood neutrophil counts and circulating inflammatory biomarkers.
METHODS
A total of 367 patients who had acute chest pain and who were admitted to our hospital for coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) from May 1, 2020 to August 31, 2020 were recruited. Among them, 256 had a cardiac troponin value above the 99th percentile upper reference limit and were diagnosed with ACS. The remaining patients (n = 111) were classified as non-ACS. The TIMI and GRACE scores were calculated at admission. The Gensini score based on CAG was used to determine atherosclerotic burden. Plasma levels of interleukin (IL)-1β, myeloperoxidase-DNA (MPO-DNA), high sensitivity C-reactive protein (hs-CRP), S100A8/A9, and BPI were measured using enzyme-linked immunosorbent assays. Correlations of plasma BPI levels with examination scores and levels of circulating inflammatory biomarkers were explored. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic efficacy of BPI for ACS and myocardial infarction.
RESULTS
Patients in the ACS group showed significantly higher plasma BPI levels compared to the non-ACS group (46.42 ± 16.61 vs. 16.23 ± 6.19 ng/mL, < 0.05). Plasma levels of IL-1β, MPO-DNA, hs-CRP, and S100A8/A9 in the ACS group were also significantly higher than those in the non-ACS group (all < 0.05). In addition, plasma BPI levels were positively correlated with the TIMI, GRACE, and Gensini scores (r = 0.176, = 0.003; r = 0.320, < 0.001; r = 0.263, < 0.001, respectively) in patients with ACS. Plasma BPI levels were also positively correlated with blood neutrophil counts (r = 0.266, < 0.001) and levels of circulating inflammatory biomarkers (IL-1β, r = 0.512; MPO-DNA, r = 0.452; hs-CRP, r = 0.554; S100A8/A9, r = 0.434; all < 0.001) in patients with ACS. ROC curve analysis revealed that the diagnostic efficacy of BPI for ACS was not inferior to that of IL-1β, MPO-DNA, hs-CRP, S100A8/A9, or blood neutrophil counts. ROC analysis also showed that the diagnostic efficacy of BPI for myocardial infarction was not inferior to that of creatine kinase (CK)-MB or cardiac troponin I.
CONCLUSION
BPI is associated with systemic inflammation in ACS and may be involved in the process of atherosclerosis and atherothrombosis. The potential of BPI as a prognostic and diagnostic biomarker for ACS should be investigated in clinical settings.
PubMed: 38933945
DOI: 10.1016/j.heliyon.2024.e32470 -
European Heart Journal Open May 2024Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and...
AIMS
Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed.
METHODS AND RESULTS
To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses.
CONCLUSION
These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
PubMed: 38933427
DOI: 10.1093/ehjopen/oeae043 -
Frontiers in Immunology 2024Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged as a critical mediator in inflammation. Disruptions within the... (Review)
Review
Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged as a critical mediator in inflammation. Disruptions within the TCA cycle lead to an accumulation of succinate in the mitochondrial matrix. This excess succinate subsequently diffuses into the cytosol and is released into the extracellular space. Elevated cytosolic succinate levels stabilize hypoxia-inducible factor-1α by inhibiting prolyl hydroxylases, which enhances inflammatory responses. Notably, succinate also acts extracellularly as a signaling molecule by engaging succinate receptor 1 on immune cells, thus modulating their pro-inflammatory or anti-inflammatory activities. Alterations in succinate levels have been associated with various inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, obesity, and atherosclerosis. These associations are primarily due to exaggerated immune cell responses. Given its central role in inflammation, targeting succinate pathways offers promising therapeutic avenues for these diseases. This paper provides an extensive review of succinate's involvement in inflammatory processes and highlights potential targets for future research and therapeutic possibilities development.
Topics: Humans; Succinic Acid; Inflammation; Signal Transduction; Animals; Citric Acid Cycle; Receptors, G-Protein-Coupled
PubMed: 38933270
DOI: 10.3389/fimmu.2024.1404441 -
Frontiers in Microbiology 2024Some recent observational studies have shown that gut microbiota composition is associated with puerperal sepsis (PS) and no causal effect have been attributed to this....
BACKGROUND
Some recent observational studies have shown that gut microbiota composition is associated with puerperal sepsis (PS) and no causal effect have been attributed to this. The aim of this study was to determine a causal association between gut microbiota and PS by using a two-sample Mendelian randomization (MR) analysis.
METHODS
This study performed MR analysis on the publicly accessible genome-wide association study (GWAS) summary level data in order to explore the causal effects between gut microbiota and PS. Gut microbiota GWAS ( = 18,340) were obtained from the MiBioGen study and GWAS-summary-level data for PS were obtained from the UK Biobank (PS, 3,940 cases; controls, 202,267 cases). Identification of single nucleotide polymorphisms associated with each feature were identified based on a significance threshold of < 1.0 × 10. The inverse variance weighted (IVW) parameter was used as the primary method for MR and it was supplemented by other methods. Additionally, a set of sensitivity analytical methods, including the MR-Egger intercept, Mendelian randomized polymorphism residual and outlier, Cochran's Q and the leave-one-out tests were carried out to assess the robustness of our findings.
RESULTS
Our study found 3 species of gut microbiota, , , and to be associated with PS. The IVW method indicated an approximately 19% decreased risk of PS per standard deviation increase with (OR = 0.81; 95% CI 0.66-1.00, = 0.047). A similar trend was also found with (OR = 0.80; 95% CI 0.66-0.97, = 0.024). However, was positively associated with the risk of PS (OR = 1.33, 95% CI: 1.07-1.67, = 0.011).
CONCLUSION
This two-sample MR study firstly found suggestive evidence of beneficial and detrimental causal associations of gut microbiota on the risk of PS. This may provide valuable insights into the pathogenesis of microbiota-mediated PS and potential strategies for its prevention and treatment.
PubMed: 38933024
DOI: 10.3389/fmicb.2024.1407324 -
BMJ Neurology Open 2024Accurate outcome predictions for patients who had ischaemic stroke with successful reperfusion after endovascular thrombectomy (EVT) may improve patient treatment and...
BACKGROUND
Accurate outcome predictions for patients who had ischaemic stroke with successful reperfusion after endovascular thrombectomy (EVT) may improve patient treatment and care. Our study developed prediction models for key clinical outcomes in patients with successful reperfusion following EVT in an Australian population.
METHODS
The study included all patients who had ischaemic stroke with occlusion in the proximal anterior cerebral circulation and successful reperfusion post-EVT over a 7-year period. Multivariable logistic regression and Cox regression models, incorporating bootstrap and multiple imputation techniques, were used to identify predictors and develop models for key clinical outcomes: 3-month poor functional status; 30-day, 1-year and 3-year mortality; survival time.
RESULTS
A total of 978 patients were included in the analyses. Predictors associated with one or more poor outcomes include: older age (ORs for every 5-year increase: 1.22-1.40), higher premorbid functional modified Rankin Scale (ORs: 1.31-1.75), higher baseline National Institutes of Health Stroke Scale (ORs: 1.05-1.07) score, higher blood glucose (ORs: 1.08-1.19), larger core volume (ORs for every 10 mL increase: 1.10-1.22), pre-EVT thrombolytic therapy (ORs: 0.44-0.56), history of heart failure (outcome: 30-day mortality, OR=1.87), interhospital transfer (ORs: 1.42 to 1.53), non-rural/regional stroke onset (outcome: functional dependency, OR=0.64), longer onset-to-groin puncture time (outcome: 3-year mortality, OR=1.08) and atherosclerosis-caused stroke (outcome: functional dependency, OR=1.68). The models using these predictors demonstrated moderate predictive abilities (area under the receiver operating characteristic curve range: 0.752-0.796).
CONCLUSION
Our models using real-world predictors assessed at hospital admission showed satisfactory performance in predicting poor functional outcomes and short-term and long-term mortality for patients with successful reperfusion following EVT. These can be used to inform EVT treatment provision and consent.
PubMed: 38932996
DOI: 10.1136/bmjno-2024-000707 -
Frontiers in Cardiovascular Medicine 2024Atherosclerosis (AS) is a complex disease caused by multiple pathological factors threatening human health-the pathogenesis is yet to be fully elucidated. In recent... (Review)
Review
Atherosclerosis (AS) is a complex disease caused by multiple pathological factors threatening human health-the pathogenesis is yet to be fully elucidated. In recent years, studies have exhibited that the onset of AS is closely involved with oral and gut microbiota, which may initiate or worsen atherosclerotic processes through several mechanisms. As for how the two microbiomes affect AS, existing mechanisms include invading plaque, producing active metabolites, releasing lipopolysaccharide (LPS), and inducing elevated levels of inflammatory mediators. Considering the possible profound connection between oral and gut microbiota, the effect of the interaction between the two microbiomes on the initiation and progression of AS has been investigated. Findings are oral microbiota can lead to gut dysbiosis, and exacerbate intestinal inflammation. Nevertheless, relevant research is not commendably refined and a concrete review is needed. Hence, in this review, we summarize the most recent mechanisms of the oral microbiota and gut microbiota on AS, illustrate an overview of the current clinical and epidemiological evidence to support the bidirectional connection between the two microbiomes and AS.
PubMed: 38932989
DOI: 10.3389/fcvm.2024.1406220 -
Pharmaceutics May 2024This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health... (Review)
Review
This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation. PDT, leveraging a photosensitizer, specific-wavelength light, and oxygen, offers targeted treatment by inducing cell death in diseased tissues while sparing healthy ones. This specificity, combined with advancements in nanoparticle technology for improved delivery, positions PDT as a promising alternative to traditional interventions. The review explores the mechanistic basis of PDT, its efficacy in preclinical studies, and the potential for enhancing plaque stability and reducing macrophage density within plaques. It also addresses the need for further research to optimize treatment parameters, mitigate adverse effects, and validate long-term outcomes. By detailing past developments, current progress, and future directions, this paper aims to highlight PDT's potential in revolutionizing atherosclerosis treatment, bridging the gap from experimental research to clinical application.
PubMed: 38931851
DOI: 10.3390/pharmaceutics16060729 -
Pharmaceuticals (Basel, Switzerland) May 2024There are a wide variety of phytochemicals collectively known as polyphenols. Their structural diversity results in a broad range of characteristics and biological... (Review)
Review
There are a wide variety of phytochemicals collectively known as polyphenols. Their structural diversity results in a broad range of characteristics and biological effects. Polyphenols can be found in a variety of foods and drinks, including fruits, cereals, tea, and coffee. Studies both in vitro and in vivo, as well as clinical trials, have shown that they possess potent antioxidant activities, numerous therapeutic effects, and health advantages. Dietary polyphenols have demonstrated the potential to prevent many health problems, including obesity, atherosclerosis, high blood sugar, diabetes, hypertension, cancer, and neurological diseases. In this paper, the protective effects of polyphenols and the mechanisms behind them are investigated in detail, citing the most recent available literature. This review aims to provide a comprehensive overview of the current knowledge on the role of polyphenols in preventing and managing chronic diseases. The cited publications are derived from in vitro, in vivo, and human-based studies and clinical trials. A more complete understanding of these naturally occurring metabolites will pave the way for the development of novel polyphenol-rich diet and drug development programs. This, in turn, provides further evidence of their health benefits.
PubMed: 38931359
DOI: 10.3390/ph17060692