Influence of nonalcoholic fatty liver disease severity on carotid adventitial vasa vasorum.

Introduction: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the world's population and encompasses a spectrum of liver conditions, from non-alcoholic steatohepatitis (NASH) to inflammation and fibrosis. In addition, NAFLD also links to extrahepatic conditions like diabetes or obesity. However, it remains unclear if NAFLD independently correlates with the onset and progression of atherosclerosis. Material and methods: This cross-sectional study aimed to explore the relationship between NAFLD severity, assessed via liver biopsy, and early atherosclerosis using adventitial vasa vasorum (VV) density. It included 44 patients with obesity (33 with steatosis, 11 with NASH) undergoing bariatric surgery. Results: Results revealed no significant differences in adventitial VV density between steatosis and NASH groups, neither in the mean values [0.759 ± 0.104 vs. 0.780 ± 0.043, P=0.702] nor left-right sides. Similarly, carotid intima-media thickness (cIMT) did not vary between these groups. Additionally, no linear correlation existed between VV density and cIMT. Only gender showed an association with VV density. Conclusion: These findings suggest that NASH severity doesn't independently drive early atherosclerosis or affects cIMT. Gender might play a role in early atherosclerotic disease in NAFLD, impacting VV density and cIMT. This highlights the need to consider other risk factors when evaluating cardiovascular risk in NAFLD patients.

The role of immune cells in different stages of atherosclerosis.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of immune cells in the intima of arteries. Experimental and clinical evidence shows that both innate and adaptive immunity orchestrate the progression of atherosclerosis. The heterogeneous nature of immune cells within atherosclerosis lesions is important. Studies utilizing high-dimensional mass spectrometry and single-cell RNA sequencing of leukocytes from atherosclerotic lesions show the diversity and adaptability of these immune cell subtypes. Their migration, compositional changes, phenotypic alterations, and adaptive responses are key features throughout atherosclerosis progression. Understanding how these immune cells and their subtypes affect atherogenesis would help to develop novel therapeutic approaches that control atherosclerosis progression. Precise targeting of specific immune system components involved in atherosclerosis, rather than broad suppression of the immune system with anti-inflammatory agents, can more accurately regulate the progress of atherosclerosis with fewer side effects. In this review, we cover the most recent advances in the field of atherosclerosis to understand the role of various immune cells on its development. We focus on the complex network of immune cells and the interaction between the innate immune system and adaptive immune system.

Impact of Probiotic Lactiplantibacillus plantarum ATCC 14917 on atherosclerotic plaque and its mechanism.

Atherosclerosis is viewed as not just as a problem of lipid build-up in blood vessels, but also as a chronic inflammatory disease involving both innate and acquired immunity. In atherosclerosis, the inflammation of the arterial walls is the key characteristic that significantly contributes to both the instability of plaque and the occlusion of arteries by blood clots. These events ultimately lead to stroke and acute coronary syndrome. Probiotics are living microorganisms that, when consumed in the right quantities, offer advantages for one's health. The primary objective of this study was to investigate the influence of Lactiplantibacillus plantarum ATCC 14917 (ATCC 14917) on the development of atherosclerotic plaques and its underlying mechanism in Apo lipoprotein E-knockout (Apoe-/- mice). In this study, Apoe-/- mice at approximately 8 weeks of age were randomly assigned to three groups: a Normal group that received a normal chow diet, a high fat diet group that received a gavage of PBS, and a Lactiplantibacillus plantarum ATCC 14917 group that received a high fat diet and a gavage of 0.2 ml ATCC 14917 (2 × 109 CFU/mL) per day for a duration of 12 weeks. Our strain effectively reduced the size of plaques in Apoe-/- mice by regulating the expression of inflammatory markers, immune cell markers, chemokines/chemokine receptors, and tight junction proteins (TJPs). Specifically, it decreased the levels of inflammatory markers (ICAM-1, CD-60 MCP-1, F4/80, ICAM-1, and VCAM-1) in the thoracic aorta, (Ccr7, cd11c, cd4, cd80, IL-1ß, TNF-α) in the colon, and increased the activity of ROS-scavenging enzymes (SOD-1 and SOD-2). It also influenced the expression of TJPs (occludin, ZO-1, claudin-3, and MUC-3). In addition, the treatment of ATCC 14917 significantly reduced the level of lipopolysaccharide in the mesenteric adipose tissue. The findings of our study demonstrated that our strain effectively decreased the size of atherosclerotic plaques by modulating inflammation, oxidative stress, intestinal integrity, and intestinal immunity.

Integrating machine learning algorithms and single-cell analysis to identify gut microbiota-related macrophage biomarkers in atherosclerotic plaques.

Objective: The relationship between macrophages and the gut microbiota in patients with atherosclerosis remains poorly defined, and effective biological markers are lacking. This study aims to elucidate the interplay between gut microbial communities and macrophages, and to identify biomarkers associated with the destabilization of atherosclerotic plaques. The goal is to enhance our understanding of the underlying molecular pathways and to pave new avenues for diagnostic approaches and therapeutic strategies in the disease. Methods: This study employed Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis on atherosclerosis datasets to identify macrophage-associated genes and quantify the correlation between these genes and gut microbiota gene sets. The Random Forest algorithm was utilized to pinpoint PLEK, IRF8, BTK, CCR1, and CD68 as gut microbiota-related macrophage genes, and a nomogram was constructed. Based on the top five genes, a Non-negative Matrix Factorization (NMF) algorithm was applied to construct gut microbiota-related macrophage clusters and analyze their potential biological alterations. Subsequent single-cell analyses were conducted to observe the expression patterns of the top five genes and the interactions between immune cells. Finally, the expression profiles of key molecules were validated using clinical samples from atherosclerosis patients. Results: Utilizing the Random Forest algorithm, we ultimately identified PLEK, IRF8, CD68, CCR1, and BTK as gut microbiota-associated macrophage genes that are upregulated in atherosclerotic plaques. A nomogram based on the expression of these five genes was constructed for use as an auxiliary tool in clinical diagnosis. Single-cell analysis confirmed the specific expression of gut microbiota-associated macrophage genes in macrophages. Clinical samples substantiated the high expression of PLEK in unstable atherosclerotic plaques. Conclusion: Gut microbiota-associated macrophage genes (PLEK, IRF8, CD68, CCR1, and BTK) may be implicated in the pathogenesis of atherosclerotic plaques and could serve as diagnostic markers to aid patients with atherosclerosis.

Gender differences in the association between changes in the atherogenic index of plasma and cardiometabolic diseases: a cohort study.

OBJECTIVE: The relationship between changes in Atherogenic Index of Plasma (AIP) and cardiometabolic diseases (CMD) in middle-aged and elderly individuals remains unclear. This study aims to explore the association between changes in AIP and CMD. METHODS: This study included 3,791 individuals aged over 45 years from CHARLS. Participants were divided into four groups using the K-Means clustering method. Cumulative AIP was used as a quantitative indicator reflecting changes in AIP. Differences in baseline data and CMD incidence rates among these four groups were compared. Multifactorial logistic regression models were used to assess the relationship between changes in AIP and CMD, and subgroup analysis and interaction tests were conducted to evaluate potential relationships between changes in AIP and CMD across different subgroups. Restricted cubic splines (RCS) were used to assess the dose-response relationship between cumulative AIP and CMD. RESULTS: Changes in AIP were independently and positively associated with CMD. In males, the risk significantly increased in class4 compared to class1 (OR 1.75, 95%CI 1.12-2.73). In females, changes in AIP were not significantly associated with CMD. Cumulative AIP was positively correlated with CMD (OR 1.15, 95%CI 1.01-1.30), with significant gender differences in males (OR 1.29, 95%CI 1.07-1.55) and females (OR 1.03, 95%CI 0.87-1.23) (p for interaction = 0.042). In addition, a linear relationship was observed between cumulative AIP and CMD in male. CONCLUSION: Substantial changes in AIP may increase the risk of CMD in middle-aged and elderly Chinese males. Dynamic monitoring of AIP is of significant importance for the prevention and treatment of CMD.

Immuno-modulatory role of baicalin in atherosclerosis prevention and treatment: current scenario and future directions.

Atherosclerosis (AS) is recognized as a chronic inflammatory condition characterized by the accumulation of lipids and inflammatory cells within the damaged walls of arterial vessels. It is a significant independent risk factor for ischemic cardiovascular disease, ischemic stroke, and peripheral arterial disease. Despite the availability of current treatments such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and lifestyle modifications for prevention, AS remains a leading cause of morbidity and economic burden worldwide. Thus, there is a pressing need for the development of new supplementary and alternative therapies or medications. Huangqin (Scutellaria baicalensis Georgi. [SBG]), a traditional Chinese medicine, exerts a significant immunomodulatory effect in AS prevention and treatment, with baicalin being identified as one of the primary active ingredients of traditional Chinese medicine. Baicalin offers a broad spectrum of pharmacological activities, including the regulation of immune balance, antioxidant and anti-inflammatory effects, and improvement of lipid metabolism dysregulation. Consequently, it exerts beneficial effects in both AS onset and progression. This review provides an overview of the immunomodulatory properties and mechanisms by which baicalin aids in AS prevention and treatment, highlighting its potential as a clinical translational therapy.

Use of Dietary Supplements Among People With Atherosclerotic Cardiovascular Disease in the United States: A Population-Based Analysis From NHANES.

BACKGROUND: Dietary supplement use is prevalent in the general US population, but little is known regarding the driving reasons for their use among those with atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: Data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to March 2020 were used to identify adults with ASCVD. Supplement use was assessed by interviewers using label review, and surveys captured self-reported reasons for use. Demographic, clinical, medication, and laboratory characteristics were compared between supplement users and nonusers. Among individuals with ASCVD in the National Health and Nutrition Examination Survey (n=965; mean age, 65 years; 56.1% men; 73.7% White individuals), 73.1% reported taking ≥1 dietary supplements, most commonly multivitamins (35.4%), vitamin D (30.8%), and fish oil (19.8%). Of those taking supplements, 47.3% report taking them under the advisement of a health professional. Nearly one fifth (17.9%) reported taking at least 1 supplement for "heart health," most commonly fish oil (11.1%), followed by CoQ10 (4.2%) and resveratrol (1.5%). Supplement users were older (68 versus 62 years; P=0.003), included more women (45.8% versus 37.7%; P=0.17), were less likely to smoke (11.0% versus 36.4%; P<0.001), had higher levels of education (P=0.005) and income (P<0.001), and higher use of statins (69.4% versus 55.8%; P=0.046). CONCLUSIONS: Supplement use is common in people with ASCVD. Among the top 3 supplements, a substantial minority were being taken under the direction of health professionals. Supplement users often report taking supplements "for heart health," despite a lack of randomized trial evidence for benefit in ASCVD, indicating a need for more patient and clinician education regarding health benefits of dietary supplements in ASCVD.

Continuity of care between dyslipidemia patients and multiple providers: A cohort study.

OBJECTIVE: This study aimed to investigate the impacts of continuity of care (COC) between patients and multiple providers, i.e., doctors and community pharmacists, on clinical and economic outcomes. METHODS: This is a retrospective cohort study and analyzed Korean national claims data for ambulatory care setting between 2007 and 2018. Patients with dyslipidemia newly diagnosed in 2008 were identified. COC between providers and patients was computed using the continuity of care index (COCI). Based on COCIs, the study patients were allocated to four groups: HM/HP, HM/LP, LM/HP, and LM/LP. Each symbol represents H for high, L for low, M for doctor, and P for pharmacist. The primary study outcome was the incidence of atherosclerotic cardiovascular disease (ASCVD). RESULTS: 126,710 patients were included. Percentages of patients in the four study groups were as follows: HM/HP 35%, HM/LP 19%, LM/HP 12%, and LM/LP 34%. During the seven-year outcome period, 8,337 patients (6.6%) developed an ASCVD, and percentages in the study groups were as follows; HM/HP 6.2%, HM/LP 6.3%, LM/HP 6.8%, and LM/LP 7.1%. After adjusting for confounding covariates, only the LM/LP group had a significantly higher risk of ASCVD than the reference group, HM/HP (aHR = 1.16 [95% confidence interval = 1.10~1.22]). The risk of inappropriate medication adherence gradually increased 1.03-fold in the HM/LP group, 1.67-fold in the LM/HP, and 2.26-fold in the LM/LP group versus the HM/HP group after adjusting for covariates. Disease-related costs were lower in the HM/HP and LM/HP groups. CONCLUSIONS: The study shows that patients with high relational care continuity with doctors and pharmacists achieved better clinical results and utilized health care less, resulting in reduced expenses. Further exploration for the group that exhibits an ongoing relationship solely with pharmacists is warranted.

Acoustic Delivery of Plasma Low-Density Lipoprotein into Liver via ApoB100-Targeted Microbubbles Inhibits Atherosclerotic Plaque Growth.

Atherosclerosis is the main risk factor for cardiovascular disease, which accounts for the majority of mortality worldwide. A significantly increased plasma level of low-density lipoprotein cholesterol (LDL-C), surrounded by a monolayer of phospholipids, free cholesterol, and one apolipoprotein B-100 (ApoB-100) in the blood, plays the most significant role in driving the development of atherosclerosis. Commercially available cholesterol-lowering drugs are not sufficient for preventing recurrent cardiovascular events. Developing alternative strategies to decrease the plasma cholesterol levels is desirable. Herein, we develop an approach for reducing LDL-C levels using gas-filled microbubbles (MBs) that were coated with anti-ApoB100 antibodies. These targeted MBApoB100 could selectively capture LDL particles in the bloodstream through forming LDL-MBApoB100 complexes and transport them to the liver for degradation. Further immunofluorescence staining and lipidomic analyses showed that these LDL-MBApoB100 complexes may be taken up by Kupffer cells and delivered to liver cells and bile acids, greatly inhibiting atherosclerotic plaque growth. More importantly, ultrasound irradiation of these LDL-MBApoB100 complexes that accumulated in the liver may induce acoustic cavitation effects, significantly enhancing the delivery of LDL into liver cells and accelerating their degradation. Our study provides a strategy for decreasing LDL-C levels and inhibiting the progression of atherosclerosis.

Interstitial Fluid Shear Stress Induces the Synthetic Phenotype Switching of VSMCs to Release Pro-calcified Extracellular Vesicles via EGFR-MAPK-KLF5 Pathway.

Phenotypic switching (from contractile to synthetic) of vascular smooth muscle cells (VSMCs) is essential in the progression of atherosclerosis. The damaged endothelium in the atherosclerotic artery exposes VSMCs to increased interstitial fluid shear stress (IFSS). However, the precise mechanisms by which increased IFSS influences VSMCs phenotypic switching are unrevealed. Here, we employed advanced numerical simulations to calculate IFSS values accurately based on parameters acquired from patient samples. We then carefully investigated the phenotypic switching and extracellular vesicles (EVs) secretion of VSMCs under various IFSS conditions. By employing a comprehensive set of approaches, we found that VSMCs exhibited synthetic phenotype upon atherosclerotic IFSS. This synthetic phenotype is the upstream regulator for the enhanced secretion of pro-calcified EVs. Mechanistically, as a mechanotransducer, the epidermal growth factor receptor (EGFR) initiates the flow-based mechanical cues to MAPK signaling pathway, facilitating the nuclear accumulation of the transcription factor krüppel-like factor 5 (KLF5). Furthermore, pharmacological inhibiting either EGFR or MAPK signaling pathway blocks the nuclear accumulation of KLF5 and finally results in the maintenance of contractile VSMCs even under increased IFSS stimulation. Collectively, targeting this signaling pathway holds potential as a novel therapeutic strategy to inhibit VSMCs phenotypic switching and mitigate the progression of atherosclerosis.

Resilient Older Subjects with Heterozygous Familial Hypercholesterolemia, Baseline Differences and Associated Factors.

Despite elevated low-density lipoprotein (LDL) cholesterol levels, some older subjects with heterozygous familial hypercholesterolemia (HeFH) do not develop atherosclerotic cardiovascular disease (ACVD) during their lifetime. The factors related to this resilient state have not been fully established. The aim of this study was to evaluate differential characteristics between older HeFH subjects with and without ACVD and factors associated with the presence of ACVD. Subjects were part of the Spanish Atherosclerosis Society Dyslipidemia Registry, and those ≥ 70 years old and with HeFH were included. Baseline characteristics of these subjects with and without ACVD were compared. A multivariate analysis was performed to assess factors associated with the presence of ACVD. A total of 2148 subjects with HeFH were included. Resilient subjects were mostly female, younger and presented fewer comorbidities with respect to the ACVD group. Subjects without ACVD had higher baseline high-density lipoprotein (HDL) cholesterol (55.8 ± 17.1 vs. 47.9 ± 15.4 mg/dL; p < 0.001) and lower lipoprotein(a) [Lp(a)] (53.4 ± 67.9 vs. 66.6 ± 85.6 mg/dL; p < 0.001) levels with respect to those in the ACVD group. Lp(a) and the presence of ≥3 risk factors were associated with the presence of ACVD.

High-density lipoprotein mimetic nano-therapeutics targeting monocytes and macrophages for improved cardiovascular care: a comprehensive review.

The prevalence of cardiovascular diseases continues to be a challenge for global health, necessitating innovative solutions. The potential of high-density lipoprotein (HDL) mimetic nanotherapeutics in the context of cardiovascular disease and the intricate mechanisms underlying the interactions between monocyte-derived cells and HDL mimetic showing their impact on inflammation, cellular lipid metabolism, and the progression of atherosclerotic plaque. Preclinical studies have demonstrated that HDL mimetic nanotherapeutics can regulate monocyte recruitment and macrophage polarization towards an anti-inflammatory phenotype, suggesting their potential to impede the progression of atherosclerosis. The challenges and opportunities associated with the clinical application of HDL mimetic nanotherapeutics, emphasize the need for additional research to gain a better understanding of the precise molecular pathways and long-term effects of these nanotherapeutics on monocytes and macrophages to maximize their therapeutic efficacy. Furthermore, the use of nanotechnology in the treatment of cardiovascular diseases highlights the potential of nanoparticles for targeted treatments. Moreover, the concept of theranostics combines therapy and diagnosis to create a selective platform for the conversion of traditional therapeutic medications into specialized and customized treatments. The multifaceted contributions of HDL to cardiovascular and metabolic health via highlight its potential to improve plaque stability and avert atherosclerosis-related problems. There is a need for further research to maximize the therapeutic efficacy of HDL mimetic nanotherapeutics and to develop targeted treatment approaches to prevent atherosclerosis. This review provides a comprehensive overview of the potential of nanotherapeutics in the treatment of cardiovascular diseases, emphasizing the need for innovative solutions to address the challenges posed by cardiovascular diseases.

The clinical role of combined circulating complement C1q and AIP for CAD with LDL-C level below 1.8mmol/L.

BACKGROUND: In the past few years, circulating complement C1q involvement in atherosclerosis has garnered growing research interest in addition to the emerging recognition of the novel lipid marker named atherogenic index of plasma (AIP). Nevertheless, among patients experiencing low-density lipoprotein cholesterol (LDL-C) levels less than 1.8mmol/L, the interplay between C1q combined with the AIP for coronary artery disease (CAD) is ambiguous. METHODS: Patients were stratified into a non-CAD and CAD group according to their coronary angiography. The association between C1q in conjunction with the AIP and CAD was explored using restricted cubic spline analyses and logistic regression models. To assess how it predicted, a receiver operating characteristic analysis was undertaken. RESULTS: A total of 7270 patients comprised 1476 non-CAD patients and 5794 patients diagnosed with CAD were analyzed. A comparison of the two groups showed that the C1q levels were notably higher compared to the CAD group, while AIP exhibited an inverse trend. Across quartiles of C1q, the AIP demonstrated a decline with increasing C1q levels, and significant differences were observed between the groups. A correlation analysis underscored a notable negative correlation between the two variables. Univariate and multivariate logistic regression analyses revealed significant associations between CAD and the C1q quartile groups/AIP. Furthermore, compared with the Q4 group, a decrease in the C1q levels corresponded to an escalation in CAD risk, with the odds ratio rising from 1.661 to 2.314. CONCLUSIONS: In conclusion, there appears to be a notable positive correlation between the combination of C1q with the AIP and CAD.

[Dynamic functional assessment of internal carotid artery tortuosity in patients with multifocal atherosclerosis]. / Dinamicheskaya funktsional'naya otsenka patologicheskikh izvitostei vnutrennikh sonnykh arterii u bol'nykh s mul'tifokal'nym aterosklerozom. Klinicheskii sluchai.

A personalized approach with attention to anamnesis and specific symptoms is necessary in patients with internal carotid artery tortuosity. Neuroimaging (especially before elective surgery) or functional stress tests following ultrasound of supra-aortic vessels may be necessary depending on medical history and complaints. In addition to standard Doppler ultrasound, these patients should undergo rotational and orthostatic transformation tests. We analyze changes in shape and hemodynamic parameters within the tortuosity area in various body positions. This is especially valuable for patients with concomitant carotid artery stenosis. The article presents a clinical case illustrating the importance of such approach.

[Functional assessment of internal carotid artery tortuosity in patients with multifocal atherosclerosis]. / Vazhnost' dinamicheskoi funktsional'noi otsenki patologicheskoi izvitosti vnutrennikh sonnykh arterii u bol'nykh s mul'tifokal'nym aterosklerozom.

The review is devoted to diagnosis and treatment of internal carotid artery tortuosity. The authors consider modern classification, epidemiology and diagnostic options using neuroimaging or ultrasound-assisted functional stress tests depending on medical history and complaints. In addition to standard Doppler ultrasound, rotational and orthostatic tests are advisable due to possible changes of local shape and hemodynamic parameters following body position changes, especially in patients with concomitant atherosclerotic stenosis. Thus, a personalized approach is especially important for treatment and diagnostics of internal carotid artery tortuosity.

Meta-analysis and transcriptomic analysis reveal that NKRF and ZBTB17 regulate the NF-κB signaling pathway, contributing to the shared molecular mechanisms of Alzheimer's disease and atherosclerosis.

INTRODUCTION: Alzheimer's disease (AD) and atherosclerosis (AS) are widespread diseases predominantly observed in the elderly population. Despite their prevalence, the underlying molecular interconnections between these two conditions are not well understood. METHODS: Utilizing meta-analysis, bioinformatics methodologies, and the GEO database, we systematically analyzed transcriptome data to pinpoint key genes concurrently differentially expressed in AD and AS. Our experimental validations in mouse models highlighted the prominence of two genes, NKRF (NF-κB-repressing factor) and ZBTB17 (MYC-interacting zinc-finger protein 1). RESULTS: These genes appear to influence the progression of both AD and AS by modulating the NF-κB signaling pathway, as confirmed through subsequent in vitro and in vivo studies. CONCLUSIONS: This research uncovers a novel shared molecular pathway between AD and AS, underscoring the significant roles of NKRF and ZBTB17 in the pathogenesis of these disorders.

Frailty and risk of systemic atherosclerosis: A bidirectional Mendelian randomization study.

BACKGROUND: Numerous observational studies have reported an association between frailty and atherosclerosis. However, the causal relationship between frailty and the occurrence of atherosclerosis in different anatomical sites remains unclear. we conducted a bidirectional Mendelian randomization (MR) study to evaluate the causal relationship between the frailty index (FI), and both systemic atherosclerosis and lipids. METHODS: We obtained summary statistics from large-scale genome-wide association studies (GWAS) of various phenotypes, including frailty (n = 175,226), coronary atherosclerosis (n = 56,685), cerebral atherosclerosis (n = 150,765), peripheral arterial disease (PAD) (n = 361,194), atherosclerosis at other sites (n = 17,832), LDL-C (n = 201,678), HDL-C (n = 77,409), and triglycerides (n = 78,700). The primary MR analysis employed the inverse variance weighted (IVW) method. Furthermore, to assess reverse causality, we employed inverse MR and multivariate MR analysis. RESULTS: Genetically predicted FI showed positive associations with the risk of coronary atherosclerosis (OR = 1.47, 95% CI 1.12-1.93) and cerebral atherosclerosis (OR = 1.99, 95% CI 1.05-3.78), with no significant association (p >0.05) applied to peripheral arterial disease and atherosclerosis at other sites. Genetically predicted FI was positively associated with the risk of triglycerides (OR = 1.31, 95% CI 1.08-1.59), negatively associated with the risk of LDL-C (OR = 0.87, 95% CI 0.78-0.97), and showed no significant association with the risk of HDL-C (p >0.05). Furthermore, both reverse MR and multivariate MR analyses demonstrated a correlation between systemic atherosclerosis, lipids, and increased FI. CONCLUSION: Our study elucidated that genetically predicted FI is associated with the risk of coronary atherosclerosis and cerebral atherosclerosis by the MR analysis method, and they have a bidirectional causal relationship. Moreover, genetically predicted FI was causally associated with triglyceride and LDL-C levels. Further understanding of this association is crucial for optimizing medical practice and care models specifically tailored to frail populations.

Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease.

People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8+ and CD4+ T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1ß, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.