In recent years, findings suggest that long noncoding RNAs (lncRNAs) are closely related to the development of atherosclerosis (AS), but there is a lack of studies on the involvement of lncRNA-regulated cytosolic burial in the regulation of AS. In this study, we investigated the mechanism by which lncRNA SCARNA8 affects macrophage cell burial to regulate AS. The cytosolic burial-associated target gene regulated by lncRNA SCARNA8 was PPARG. LncRNA SCARNA8 was increased in the carotid unstable plaque group, whereas PPARG was decreased. Ox-LDL led to the up-regulation of lncRNA SCARNA8 expression and apoptosis in Raw264.7 cells in a time-, concentration-dependent manner. Knockdown of lncRNA SCARNA8 upregulated PPARG and reduced apoptosis in Raw264.7 cells. In addition, knockdown of lncRNA SCARNA8 improved the stability of atherosclerotic plaques by promoting cellular burial of Raw264.7 cells. LncRNA SCARNA8 is a key regulator of plaque vulnerability, and targeting lncRNA SCARNA8 May provide a novel means for the prevention and treatment of AS.

This study investigated the impact of maternal high-fat diet on vascular function and endothelial homeostasis in offspring. We found that offspring exposed to maternal high-fat diet exhibited elevated blood pressure, impaired abdominal aortic vascular function, and endothelial homeostasis imbalance. These changes were accompanied by increased levels of reactive oxygen species (ROS) and upregulation of pro-inflammatory cytokines (including IL-1β, TNF-α, IL-6, and IL-10). Treatment with NLRP3 or IL-1β inhibitors prevented the deterioration in vascular function, reduced endothelial NO production, and inflammation induced by maternal high-fat diet exposure compared to the control group. The findings suggest that during pregnancy, mitigating the vascular impairments in offspring induced by maternal high-fat diet can be achieved by inhibiting the NLRP3/IL-1β pathway.

Vascular inflammation is a key process in the pathogenesis of atherosclerosis, which is regulated by NF-κB pathway. Yiqi Wenyang decoction (YQWY), a Traditional Chinese medicine (TCM) formula, has anti-inflammatory properties and may inhibit this pathway, potentially offering anti-atherosclerotic effects.

The purpose of this study is to investigate the effects of YQWY on atherosclerosis and the underlying mechanism. Materials and methods: ApoE-/- mice were fed a Western diet and administered with YQWY (low or high dose), atorvastatin, or vehicle for 13 weeks. The size of atherosclerotic plaques was assessed using ORO staining. Vascular inflammation was evaluated with IF or IHC staining. The mechanisms and signaling pathways underlying the effect of YQWY on vasculature were studied using transcriptomic analysis and were validated in vitro in endothelial cells and macrophages.

YQWY attenuated atherosclerotic plaque development which was associated with reduced vascular inflammation as demonstrated by transcriptomic analysis of aorta. This was verified by reduced expression of proinflammatory chemokines, adhesion molecules, and inflammatory cytokines in aortas from YQWY-treated mice at both mRNA and protein levels. Mechanistically, YQWY suppressed NF-κB activation in endothelial cells and, to a lesser extent, macrophages possibly.

YQWY protects against vascular inflammation and atherosclerosis by suppressing NF-κB pathway, suggesting the potential of YQWY and its active ingredients as novel anti-atherosclerotic therapeutics.

In epidemiological studies, higher leukocyte and platelet counts are associated with increased risk of cardiovascular events. Effects of testosterone replacement therapy (TRT) on leukocyte subsets and platelets in men with hypogonadism and association of circulating leukocyte subtypes and platelets during TRT with cardiovascular events remain unknown.

In the TRAVERSE Trial, 5,204 men, 45-80 years with hypogonadism and preexisting or increased risk of cardiovascular disease (CVD) were randomized to transdermal testosterone or placebo gel daily for up to 5 years. We determined the effect of TRT on neutrophils, monocytes, lymphocytes and platelets and association of changes in leukocyte subtypes and platelets with risk of major adverse cardiovascular (MACE) and venous thromboembolism (VTE) events.

TRT was associated with significantly greater increase in neutrophils and monocytes, and greater decrease in lymphocytes and platelets than placebo. Changes in neutrophil (odds ratio for 1 SD increase in cell count (OR) 1.32 [1.01, 1.73]) and monocyte (OR 1.39 [1.08, 1.79]) counts were associated with increased risk of VTE, accounting for TRT. Neutrophil and monocyte counts at baseline and on-treatment were also associated with increased risk of MACE, adjusting for treatment (baseline: neutrophils OR 1.18 [1.06,1.31], monocytes OR 1.16 [1.05,1.29]; on-treatment neutrophils: OR 1.25 [1.12, 1.40]; monocytes: OR 1.18 [1.06,1.31]).

TRT increased circulating neutrophils and monocytes and decreased lymphocytes and platelets in men with hypogonadism. Changes in monocyte and neutrophil counts were associated with increased risk of VTE. Neutrophil and monocyte counts should be considered when evaluating VTE risk in hypogonadal men treated with TRT.

URL:https://clinicaltrials.gov/study/NCT03518034. Unique identifier: NCT03518034. The study was initially registered on March 5, 2018, and the first participant was enrolled on May 23, 2018.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid accumulation and inflammation. Macrophage phenotypic transformation plays a critical role in AS progression. Aryl hydrocarbon receptor (AhR) has been proved to regulate the phenotype of macrophages. This study investigates the role and molecular mechanism of AhR activation by its endogenous ligand, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) attenuates AS.

We employed Western blotting to analyze the expression of AhR, NF-κB, and lipocalin-2 (LCN2). Flow cytometry and immunofluorescence staining were used to assess the phenotype of macrophages. Plaque progression was evaluated using pathological staining. Transcriptome sequencing was utilized to explore the potential mechanism by which AhR promotes macrophage phenotypic transformation. CUT&Tag-qPCR and lentivirus infection confirmed that the AhR/NF-κB/LCN2 pathway regulates macrophage polarization.

Activation of AhR by ITE reduced plaque area and inhibited lipid deposition. ITE significantly increased the number of M2-like macrophages both in vivo and in vitro. Transcriptome sequencing identified LCN2 as a key target for AhR-mediated macrophage M2-like polarization. Furthermore, AhR activation suppressed the NF-κB/LCN2 pathway.

Our findings reveal that AhR promotes the macrophages to exhibit M2-like characteristics to attenuate AS by inhibiting the NF-κB/LCN2 pathway. These results suggest that AhR may serve as a novel therapeutic target for AS.

Xiexin Tang (XXT) is a classic Chinese medicine formula that can be used to treat Atherosclerosis (AS). This study aimed to investigate the mechanism by which XXT regulated AS lipid levels. Firstly, the mixture components of XXT were analyzed by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Then, the AS model based on Apolipoprotein E knockout (ApoE-/-) mice was established. Cytokines related to lipid metabolism and bile acid metabolism were detected by Quantitative Real-time PCR (qRT-PCR). 16S rDNA gene sequencing was performed to analyze differential bacterial populations, and the mechanism of XXT regulation of bile acids affecting lipid metabolism was further explored by targeted metabolomics. Further, antibiotic-treated mice were used to investigate the role of gut microbiota in the anti-AS effect of XXT. The results showed that XXT attenuated the lipid levels and reversed the abnormal elevation of cytokines, such as hepatic lipid metabolism and inflammatory reaction in AS mice. XXT also repaired the gut barrier damage and reversed gut microbiota disorders in AS mice. Furthermore, the metabolic levels of bile acids were reshaped by XXT. Whereas, in the absence of gut microbiota, XXT failed to attenuate lipid levels and inhibit the expression of cytokines related to inflammation and bile acid metabolism in AS mice and failed to play a role in ultimately treating AS. In conclusion, XXT could effectively inhibit the inflammatory reaction and lipid accumulation in AS mice, and this effect was closely related to its remodeling of gut microbiota to regulate bile acid metabolism.

Psoriasis is an immune-mediated pro-inflammatory skin condition that is associated with an increase in risk factors for cardiovascular disease, risk of ischemic heart disease, and cardiovascular death. Despite this, traditional modifiable atherosclerotic cardiovascular disease (ASCVD) risk factors are underdiagnosed and undertreated in patients with psoriasis.

At a cellular level, psoriasis and atherosclerosis are driven by a host of shared inflammatory pathways, such as pro-inflammatory cytokines (TNF, IL-6), immune cells, and platelets which act synergistically to drive endothelial damage and atherosclerosis progression.

Optimal prevention of cardiovascular disease in psoriasis centers around modifying known risk factors for the development of ASCVD and emerging data highlight the promise of treating inflammation to further decrease the risk of ASCVD.

The likelihood of a plaque to cause an acute coronary syndrome (ACS) depends on several factors, both lesion- and patient-related. One of the most investigated and established contributing factors is the presence of high-risk or "vulnerable plaque" characteristics, which have been correlated with increased incidence of major adverse cardiovascular events (MACE). The recognition, however, that a significant percentage of vulnerable plaques do not result in causing clinical events has led the scientific community towards the more multifaceted concept of "vulnerable patients". Incorporating the morphological features of an atherosclerotic plaque into its hemodynamic surroundings can better predict the chance of its disruption, as altered fluid dynamics play a significant role in plaque destabilization. The advances in coronary imaging and the field of computational fluid dynamics (CFD) can contribute to develop more accurate lesion- and patient-related ACS prediction models that take into account both the morphology of a plaque and the forces applied upon it. The aim of this review is to provide the latest data regarding the aforementioned predictive factors as well as relevant preventive measures.

Stroke significantly impacts global health, being a primary cause of disability, dementia, and mortality. The interplay of nutritional deficiency and systemic inflammation plays a pivotal role in determining stroke outcomes. While the Prognostic Nutritional Index (PNI) and the Advanced Lung Cancer Inflammation Index (ALI) have been recognized for their prognostic value in various diseases, their relevance in stroke prognosis necessitates further exploration.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018, analyzing 908 stroke survivors to examine the associations between PNI, ALI, and mortality outcomes. Weighted Cox proportional hazards models were applied to assess the associations, controlling for demographic and health-related variables. Kaplan-Meier curves and restricted cubic splines were used to evaluate survival differences and non-linear relationships, respectively. Additionally, subgroup and sensitivity analyses were conducted to verify the robustness of the associations.

In our cohort, elevated PNI was associated with significantly lower risks of all-cause mortality (Hazard Ratio [HR]: 0.53, 95 % Confidence Interval [CI]: 0.37-0.75, p < 0.001) and cardiovascular mortality (HR: 0.60, 95 % CI: 0.38-0.94, p = 0.028). Similarly, higher ALI levels correlated with a reduced risk of all-cause mortality (HR: 0.53, 95 % CI: 0.37-0.72, p < 0.001), though its impact on cardiovascular mortality did not reach statistical significance after adjustment. Subgroup analysis revealed that gender, age, and diabetes status modulated the relationship between PNI/ALI and mortality outcomes, with significant interactions observed especially in diabetic patients (PNI: P for interaction = 0.025 and ALI: P for interaction = 0.007).

This study confirms that higher PNI and ALI are associated with lower all-cause mortality in stroke survivors. Elevated PNI also reduces cardiovascular mortality risk. Gender, age, and diabetes status influence these associations. These findings highlight the importance of monitoring nutritional and inflammatory status in stroke recovery.

Atherosclerosis, driven by inflammation, is a leading cause of cardiovascular events. Recent clinical trials have highlighted the therapeutic potential of anti-inflammatory treatments. Consequently, colchicine is being recommended for secondary prevention in current guidelines, although the drug's mechanistic actions are not fully understood.

To this end, we conducted a multiomic investigation of colchicine's effect on human carotid plaques. Sections from endarterectomy specimens were exposed to colchicine at concentrations of 2 ng/ml and 10 ng/ml ex vivo for 24 h and compared to untreated segments of the same plaque. Gene expression changes were analyzed by bulk RNA sequencing, and plaque secretomes underwent mass spectrometry for proteomic analysis. In situ cell proliferation was assessed by histology.

Our data indicate, that colchicine suppresses neutrophil and platelet degranulation and activation, collagen degradation and atheromatous plaque macrophage proliferation in a dose-dependent manner in human plaques, while stimulating myofibroblast activation. Unexpectedly, interleukine (IL)-1beta release from colchicine treated plaques was not reduced. These results indicate that the inflammasome may not be the predominant target of low-dose colchicine in human carotid artery plaques.

Our study identifies multifactorial pathways through which colchicine, the first cardiovascular guideline-recommended anti-inflammatory drug, predominantly acts on human atherosclerotic lesions beyond the inflammasome. Targeting neutrophil and platelet degranulation, collagen degradation and macrophage proliferation, selectively, may provide substantial therapeutic benefit in atherosclerotic cardiovascular disease without colchicine's undesired side effects.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical player in cancer pathogenesis. Concurrently, inflammation, a key biological response to tissue injury or infection, significantly influences cancer development and progression. The interplay between ferroptosis and inflammation represents a promising yet underexplored area of research. This review synthesizes recent advances in understanding the molecular mechanisms governing their interaction, emphasizing how ferroptosis triggers inflammatory responses and how inflammatory mediators, such as TNF-α, regulate ferroptosis through iron metabolism and lipid peroxidation pathways. Key molecular targets within the ferroptosis-inflammation axis, including GPX4, ACSL4, and the NF-κB signaling pathway, offer therapeutic potential for cancer treatment. By modulating these targets, it may be possible to enhance ferroptosis and fine-tune inflammatory responses, thereby improving therapeutic outcomes. Additionally, this review explores the broader implications of targeting the ferroptosis-inflammation interplay in disease treatment, highlighting opportunities for developing innovative strategies to combat cancer. By bridging the gap in current knowledge, this review provides a comprehensive resource for researchers and clinicians, offering insights into the therapeutic potential of this intricate biological relationship.

Hypercholesterolemia has been associated with cognitive dysfunction and neurodegenerative diseases. Moreover, this metabolic condition disrupts the blood-brain barrier, allowing low-density lipoprotein (LDL) to enter the central nervous system. Thus, we investigated the effects of LDL exposure on mitochondrial function in a mouse hippocampal neuronal cell line (HT-22). HT-22 cells were exposed to human LDL (50 and 300 μg/mL) for 24 h. After this, intracellular lipid droplet (LD) content, cell viability, cell death, and mitochondrial parameters were assessed. We found that the higher LDL concentration increases LD content compared with control. Both concentrations increased the number of Annexin V-positive cells, indicating apoptosis. Moreover, in mitochondrial parameters, the LDL exposure on hippocampal neuronal cell line leads to a decrease in mitochondrial complexes I and II activities in both concentrations tested and a reduction in Mitotracker™ Red fluorescence and Mitotracker™ Red and Mitotracker™ Green ratio in the higher concentration, indicating mitochondrial impairment. The LDL incubation induces mitochondrial superoxide production and decreases superoxide dismutase activity in the lower concentration in HT-22 cells. Finally, LDL exposure increases the expression of genes associated with mitochondrial fusion (OPA1 and mitofusin 2) in the lower concentration. In conclusion, our findings suggest that LDL exposure induces mitochondrial dysfunction and modulates mitochondrial dynamics in the hippocampal neuronal cells.

Clonal hematopoiesis (CH) has been the focus of many research efforts in the last years and has emerged as a risk modifier for cardiovascular disease morbidity and mortality. While substantial evidence has accumulated regarding its impact on arterial system diseases, the connection with venous thrombosis has only recently been explored. Both clinical and preclinical evidence suggest that the magnitude and mechanism underlying the association of CH with cardiovascular events vary depending on the specific mutated gene involved, indicating a causal link between CH and thrombosis development, not only in the arterial system, particularly in the context of atherosclerosis, but also in venous thrombosis. Although this growing body of knowledge has driven translational research and provided insights for improving clinical management, several questions remain unanswered. This review aims to summarize the available evidence on the link between CH and thrombosis, while highlighting the gaps that need to be addressed in future research.

Apolipoprotein B (apoB) is the main structural protein of LDLs, triglyceride-rich lipoproteins and lipoprotein(a), and is crucial for their formation, metabolism and atherogenic properties. In this Review, we present insights into the role of apoB-containing lipoproteins in atherogenesis, with an emphasis on the mechanisms leading to plaque initiation and growth. LDL, the most abundant cholesterol-rich lipoprotein in plasma, is causally linked to atherosclerosis. LDL enters the artery wall by transcytosis and, in vulnerable regions, is retained in the subendothelial space by binding to proteoglycans via specific sites on apoB. A maladaptive response ensues. This response involves modification of LDL particles, which promotes LDL retention and the release of bioactive lipid products that trigger inflammatory responses in vascular cells, as well as adaptive immune responses. Resident and recruited macrophages take up modified LDL, leading to foam cell formation and ultimately cell death due to inadequate cellular lipid handling. Accumulation of dead cells and cholesterol crystallization are hallmarks of the necrotic core of atherosclerotic plaques. Other apoB-containing lipoproteins, although less abundant, have substantially greater atherogenicity per particle than LDL. These lipoproteins probably contribute to atherogenesis in a similar way to LDL but might also induce additional pathogenic mechanisms. Several targets for intervention to reduce the rate of atherosclerotic lesion initiation and progression have now been identified, including lowering plasma lipoprotein levels and modulating the maladaptive responses in the artery wall.

Macrophages make up a substantial portion of the stromal compartment of the heart in health and disease. In the past decade, the origins of these cardiac macrophages have been established as two broad populations derived from either embryonic or definitive haematopoiesis and that can be distinguished by the expression of CC-motif chemokine receptor 2 (CCR2). These cardiac macrophage populations are transcriptionally distinct and have differing cell surface markers and divergent roles in cardiac homeostasis and disease. Embryonic-derived CCR2- macrophages are a tissue-resident population that participates in tissue development, repair and maintenance, whereas CCR2+ macrophages are derived from definitive haematopoiesis and contribute to inflammation and tissue damage. Studies from the past 5 years have leveraged single-cell RNA sequencing technologies to expand our understanding of cardiac macrophage diversity, particularly of the monocyte-derived macrophage populations that reside in the injured and diseased heart. Emerging technologies in spatial transcriptomics have enabled the identification of distinct disease-associated cellular neighbourhoods consisting of macrophages, other immune cells and fibroblasts, highlighting the involvement of macrophages in cell-cell communication. Together, these discoveries lend new insights into the role of specific macrophage populations in the pathogenesis of cardiac disease, which can pave the way for the identification of new therapeutic targets and the development of diagnostic tools. In this Review, we discuss the developmental origin of cardiac macrophages and describe newly identified cell states and associated cellular neighbourhoods in the steady state and injury settings. We also discuss various contributions and effector functions of cardiac macrophages in homeostasis and disease.

Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural-functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.

Recent studies have shown that chronic inflammation in atherosclerotic (ATH) lesions is due to an inability to resolve the inflammatory response. We evaluated the therapeutic potential of specialized pro-resolving mediators (SPMs) incorporated into biomimetic lipid nanoemulsions covered with macrophage membranes (Bio-LN/SPMs) to enhance their stability, targeting, and bioactivity in resolving atherosclerotic plaque inflammation. We utilized both in vitro and in vivo experimental models to test this hypothesis. In vitro, we found that Bio-LN/SPMs significantly reduced the inflammatory markers VCAM-1, MCP-1 in TNF-α-activated endothelial and smooth muscle cells, and iNOS, and NLRP3 in LPS-activated macrophages. In contrast, free SPMs exhibited a more modest effect. In vivo, the i.v. administration of Bio-LN/SPMs in ApoE-deficient mice with progressive atherosclerotic lesions developed after administration for 4 and 8 weeks of a high-fat diet, reduced plasma triglycerides, improved renal function, and decreased plasma proteins associated with complement activation and inflammation (i.e. C4d, C5b-9, IL-6, and MCP-1) to a greater extent than other treatment groups. Bio-LN/SPMs also affected circulated monocyte subpopulations by increasing the percentage of anti-inflammatory Ly6Clow monocytes and reducing that of pro-inflammatory Ly6Chigh monocytes. Additionally, they promoted the transition of macrophages in atherosclerotic plaques to a reparative M2 phenotype. They decreased the production of TNF-α, IL-1β, and IL-6 cytokines, along with lipid deposits in the aorta of ApoE-deficient mice. These findings demonstrate the improved therapeutic efficacy of Bio-LN/SPMs compared to unincorporated SPMs and standard nanoemulsions (LN/SPMs), emphasizing their potential as a novel approach for treating atherosclerosis and other inflammatory diseases.

Residual inflammation drives atherogenesis to atherosclerosis and myocardial infarction, which triggers acute inflammation. In preclinical studies, polyunsaturated fatty acids-derived specialized pro-resolving mediators (SPMs) have been shown to promote recovery after myocardial infarction (MI), in contrast to proinflammatory lipid mediators (PIMs). However, the dynamic changes of lipid mediators after ST-elevation myocardial infarction (STEMI), particularly after percutaneous coronary intervention (PCI) and respective gene transcripts, are poorly understood. Therefore, the study aimed to assess the early dynamic changes in circulating lipid mediators and lipid pathway transcripts in patients with STEMI who undergo PCI. In this prospective observational clinical study, patients with STEMI (n = 10) and control subjects (n = 6) were included. Plasma samples for lipid mediator profiling (targeted oxylipids) and whole blood for inflammation-related transcript expression were collected at baseline before PCI, 2-, and 24-h post-PCI. A total of 10 patients with STEMI received PCI with a mean age of 53.3 yr, 90% male. Linoleic acid and docosapentaenoic acid levels were higher in patients with STEMI. A subset of PIM levels [hydroxyeicosatetraenoic acids, prostaglandin (PG)E2] was elevated at the baseline, with a subsequent decrease in circulating levels at 2 h after PCI [thromboxanes, leukotriene B4 (LTB4), 20-hydroxy-LTB4]. A subset of SPM levels was elevated at the baseline of STEMI suggestive overlap of inflammation-resolution signaling. The temporal kinetics of lipid mediators showed that both the initiation of inflammation and the resolution process start simultaneously and continue as an endogenous repair mechanism during STEMI. Therefore, approaches to increase these endogenous bioactive resolution mediators content and/or efficacy before PCI should be considered in treating patients with MI.NEW & NOTEWORTHY Polyunsaturated fatty acids-derived SPMs are decisive in myocardial infarction (MI) recovery, contrasting with proinflammatory lipid mediators (PIMs). A study on early lipid changes post-percutaneous coronary intervention (PCI) in patients with STEMI shows baseline elevation and post-PCI decrease in PIMs, whereas some SPM levels remain elevated. Findings highlight simultaneous inflammation and resolution in STEMI, emphasizing the need to enhance endogenous repair processes before PCI for better MI treatment.

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. It is considered to be a premalignant state that predisposes individuals to an increased risk of cancers. Recently, emerging evidence has demonstrated a strong association between CH and both the incidence and mortality of cardiovascular diseases (CVD), with the relative risks being comparable to those attributed to traditional cardiovascular risk factors. In addition, CH has been suggested to play a role in CVD and anti-cancer treatment-related cardiotoxicity amongst cancer survivors. Moreover, certain forms of chemotherapy and radiation therapy have been shown to promote the clonal expansion of specific CH-related mutations. Consequently, CH may play a substantial role in the realm of cardio-oncology. In this review, we discuss the association between CH with cancer and CVD, with a special focus on anti-cancer treatment-related cardiotoxicity, discuss possible future research avenues and propose a systematic approach for clinical practice.

Advances in genomic technologies have significantly enhanced our understanding of both monogenic and polygenic etiologies of cardiovascular disease. In this review, we explore how the utilization of genomic information is bringing personalized medicine approaches to the forefront of cardiovascular disease management. We describe how genomic data can resolve diagnostic uncertainty, support cascade screening, and inform treatment strategies. We discuss how genome-wide association studies have identified thousands of genetic variants associated with polygenic cardiovascular diseases, and how integrating these insights into polygenic risk scores can enhance personalized risk prediction beyond traditional clinical algorithms. We detail how pharmacogenomics approaches leverage genotype information to guide drug selection and mitigate adverse events. Finally, we present the paradigm-shifting approach of gene therapy, which holds the promise of being a curative intervention for cardiovascular conditions.

Inflammatory bowel diseases (IBD) have been associated with an increased long-term risk of coronary artery disease due to chronic systemic inflammation.

To evaluate the risk of major adverse cardiovascular events (MACE) after coronary interventions.

In this nationwide cohort study of adults undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) (2012-2022), patients with IBD were propensity score-matched 1:10 to comparators without IBD. The primary outcome was MACE, a composite of acute myocardial infarction, stroke, hospitalisation for heart failure, or mortality. Secondary outcomes included each MACE component, 30-day all-cause readmission, revascularisation and in-hospital outcomes including intensive care unit admission and length of hospital stay. We calculated hazard ratios (HRs) and incidence rates (IRs) using Cox proportional hazards modelling.

We included 987 patients with IBD and 9571 matched comparators. After a median follow-up of 3.5 years, MACE occurred in 488 patients with IBD (49.4%, IR: 96.5/10,000 person-years [PY]) and in 3857 matched comparators (40.3%, IR: 68.9/10,000 PY); HR 1.37 (95% CI, 1.24-1.52). This equates to one additional MACE for every 36 patients with IBD over 10 years. The risk of each MACE component was increased, except for stroke. There were no differences between IBD subtypes or coronary intervention (PCI vs. CABG). Risks were highest in older individuals and elective interventions.

Patients with IBD were at 37% higher risk of MACE after coronary intervention, indicating a need for intensified cardiovascular risk reduction in these high-risk individuals.

NLRP3 inflammasome is considered a critical actor in the inflammatory process of coronary artery disease. Increased expression of NLRP3 inflammasome components has been reported in patients with acute coronary syndrome, but whether this persists beyond the acute phase is less known. We performed a prospective study to investigate whether basal and/or exercise-induced NLRP3 inflammasome components were elevated in patients with chronic coronary syndrome (CCS).

Patients (n = 81) underwent exercise stress tests twice: 3-4 weeks and 3-6 months after a major coronary event, whereas controls (n = 30) performed it once. Concentrations of interleukin(IL)-18, IL-1Ra and IL-6 were measured before and 30 min after exercise. Genes related to NLRP3 inflammasome and NFκB signaling pathways were measured in blood mononuclear cells before and after exercise. On the first visit, patients were prescribed an exercise-based cardiac rehabilitation program. Physical activity levels were reported on both visits.

Patients were clinically stable and exhibited increased exercise capacity as well as increased self-reported physical activity between visits. Basal plasma levels of IL-18, as well as exercise-induced levels of IL-18 and IL-1Ra, were higher in patients compared with controls on both visits. Also, basal gene expression of NLRP3 was higher in patients, as were several NFκB-related genes. After exercise, gene expression related to NLRP3 inflammasome activation, in particular P2RX7, was higher in patients on both visits.

Up to 6 months after a coronary event, patients exhibited an increase in NLRP3 inflammasome-related components that was even more pronounced after acute exercise, compared with controls. The results indicate that a primed NLRP3 inflammasome system is maintained despite clinical stability and best available therapy, highlighting the need to further combat inflammation in patients with CCS.

Endoplasmic reticulum (ER) stress pathways contribute to atherosclerosis progression. Recently, we developed Kyoto University Substance (KUS) 121, which selectively inhibits ATPase activities of valosin-containing protein (VCP), consequently conserving intracellular ATP consumption and mitigating ER stress. This study evaluated the efficacy of KUS121 in atherosclerosis.

KUS121 was administered daily to Apoe-/- mice fed a Western diet (WD) for 8 weeks. KUS121 treatment resulted in a 40-50 % reduction in atherosclerosis progression. Interestingly, we observed that C/EBP homologous protein (Chop), a well-established ER stress marker, was predominantly expressed in plaque endothelium. In human EA.hy926 endothelial cells, KUS121 prevented ER stress-induced apoptosis and downregulated the Inositol-requiring enzyme 1 alpha (IRE1α)-associated inflammatory pathways. Consistent with these in vitro findings, KUS121 treatment significantly reduced endothelial apoptosis, as shown by TUNEL and cleaved caspase-3 staining, and inflammation, as demonstrated by immunostaining of Nuclear factor kappa B (NF-κB) and Intercellular adhesion molecule (Icam) 1 at plaque endothelium. We also demonstrated that KUS121 maintained ATP levels in EA.hy926 cells and atherosclerotic plaque lesions using single-wavelength and the FRET-based fluorescent ATP sensors. Supplementation of intracellular ATP by methyl pyruvate attenuated ER stress-induced apoptotic and inflammatory pathways in endothelial cells, similar to KUS121. Besides affecting ER stress, KUS121 also reduced inflammation even without ER stress by inhibiting glycolysis through increased intracellular ATP levels in LPS-treated EA.hy926 cells.

KUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels, leading to the attenuation of ER stress and glycolysis in plaque endothelium.

This paper explores emerging therapies in polycythemia vera and essential thrombocythemia, focusing on thrombosis as a driver of disease progression leading to myelofibrosis, blast phase, second cancers, and mortality. While the thrombosis rate in high-risk patients has declined, it remains persistently high in low-risk individuals, with most events being arterial. Inflammation driven by JAK2 V617F mutation plays a primary role in pathogenesis, and mounting evidence suggests arterial thrombosis itself can fuel a self-sustaining cycle of inflammation, thereby accelerating hematologic and systemic complications. Early intervention with cytoreductive and anti-inflammatory drugs may not only prevent incidental thrombosis but also disrupt this inflammatory circuit.

As a novel indicator reflecting metabolic status and visceral adiposity distribution, the cardiometabolic index (CMI) has gained attention in cardiovascular risk stratification. This investigation employed optical coherence tomography (OCT) to examine potential associations between CMI and vulnerable plaque, as well as the role of inflammation.

This study conducted a cross-sectional analysis of 270 acute coronary syndrome (ACS) patients who had OCT imaging evaluation. Patients were categorized based on CMI tertiles, with CMI calculated using the formula [waist (cm)/height (cm)]×[triglycerides (mmol/L)/HDL-C (mmol/L)]. OCT was used to assess plaque events in culprit lesions and plaque components in non-culprit lesions, and inflammatory markers were measured. A mediation analysis framework was implemented to investigate inflammatory pathways in CMI-vulnerable plaque relationships.

CMI tertiles were linked to vulnerable plaque traits: thin-cap fibroatheromas (TCFA), macrophages (Tertiles1 vs. Tertiles2 vs. Tertiles3, TCFA: 10.0% vs. 20.0% vs. 26.7%, P = 0.016; macrophages: 17.8% vs. 28.9% vs. 36.7%, P = 0.019). Multivariate regression demonstrated CMI elevation independently predicted a higher prevalence of TCFA (OR:1.40, 95%CI: 1.25-2.89, P = 0.003), more macrophage infiltration (OR:1.61, 95% CI:1.09-2.37, P = 0.017), reduced FCT (β:-30.65, 95% CI:-50.72-10.57, P = 0.003), and enlarged maximum lipid arc (β:20.78, 95% CI:6.55-35.01, P = 0.004). Moreover, CMI was positively related to hsCRP, WBC, and neutrophils. Mediation analysis revealed that hsCRP mediated about 17.0% of the association between CMI and minimum FCT [Indirect effect=-5.21, 95% CI=(-12.70, -1.27), P = 0.016].

CMI is a key forecaster of vulnerable plaque in patients with ACS. Systemic inflammation is associated with the relationship between CMI and vulnerable plaque features, suggesting a potential mechanistic link.

T helper 1 (Th1) cell initiation pathways are well characterized; however, those regulating their contraction are less understood. Here, we define a CD4+ T cell-autonomous pathway in which complement C5 orchestrated a shift from prostaglandin E2 (PGE2) dominance to enhanced prostacyclin (PGI2) production via activation of C5a receptor 2 (C5aR2). This pivot in lipid mediators induced autocrine signaling through the PGI2 receptor and expression of the interleukin-1 (IL-1) decoy IL-1 receptor type 2 (IL-1R2), which sequestered Th1 cell-driving intrinsic IL-1β, facilitating Th1 cell contraction. Disruption of this C5aR2-PGI2-R axis was a hallmark of pathologically persistent Th1 cell activity in inflammatory conditions, including cryopyrin-associated periodic syndromes (CAPS), Crohn's disease, and rheumatoid arthritis. Rebalancing this axis through selective PGE2 synthase inhibition rectified the hyperactive Th1 cell phenotype in vitro in T cells from individuals with CAPS. Therefore, complement is a key controller of prostanoid metabolism, and the latter is an intrinsic-and potentially druggable-checkpoint for the cessation of Th1 cell effector responses.

Atherosclerosis remains a leading disease posing significant threats to human health and life. Oxidative stress plays a critical role in the initiation of early atherosclerosis. Ginsenoside Rb3 has been shown to exert potential therapeutic effects against atherosclerosis due to its antioxidant properties. However, its clinical utility remains constrained to the nanometer scale, offering insufficient targeting capability for atherosclerosis treatment. To address this limitation, we designed a novel Rb3-loaded microbubble system Rb3NPs@MBs. This microbubble system effectively encapsulates Rb3 nanoparticles and, via ultrasound-targeted microbubble destruction (UTMD), facilitates their targeted accumulation in the aortic arch of atherosclerotic mice. Subsequently, Rb3NPs@MBs reduce oxidative stress, attenuate endothelial cell apoptosis and foam cell formation, and ultimately diminish plaque development at the lesion site. This strategy holds promise as a therapeutic approach for atherosclerosis. These findings suggest that Rb3NPs@MBs represent a promising therapeutic strategy for atherosclerosis.

Postbariatric hypoglycaemia (PBH) is a complex medical condition with a significant impact on patients' quality of life. The underlying mechanisms remain to be elucidated. We have shown that food ingestion increases IL-1β and subsequently stimulates insulin secretion. We therefore hypothesised that overactivation of the IL-1β pathway could lead to PBH by promoting excessive insulin secretion after a meal. In a proof-of-concept study, we have shown that acute treatment with the IL-1 receptor antagonist anakinra can attenuate PBH after a single liquid mixed meal. This study aims to validate this therapeutic approach over a longer period of time using the long-acting anti-IL-1β antibody canakinumab.

In this prospective, randomised, double-blind, placebo-controlled, multicentre trial, we plan to enrol 62 adult patients after bariatric surgery with frequent, postprandial hypoglycaemia (ie, <3.0 mmol/L and at least five hypoglycaemic episodes per week). Eligible subjects will be randomised to receive either single-dose 150 mg canakinumab (Ilaris, Novartis) subcutaneously (s.c.) or matched placebo (1.0 mL physiologic saline). For 28 days, patients are required to wear a blinded continuous glucose monitoring device (CGMS, Dexcom G6) and use a diary to track their hypoglycaemic episodes. Primary outcomes include health-related quality of life, measured by the SF-36, as well as postprandial hypoglycaemic events (glucose <3.0 mmol/L). A significant improvement in any one of these outcomes will be considered sufficient to demonstrate the clinical superiority of canakinumab over placebo. Secondary outcomes include patient-oriented measures such as postprandial hypoglycaemic symptoms, hypoglycaemia unawareness, fear of hypoglycaemia, as well as metabolic measures and safety assessments.

The trial was approved by the Cantonal Ethics Committee 'Ethikkommission Nordwest- und Zentralschweiz' in January 2022 (#2021-02325), as well as by Swissmedic in April 2022 (#701280). Current, approved protocol version 1.3 of 28.03.2023. The study is actively recruiting. Results will be published in a relevant scientific journal and communicated to participants and relevant institutions through dissemination activities. Individual data are accessible on request.

The study is registered with the www.

gov registry (NCT05401578) and the Swiss National Clinical Trials Portal (SNCTP) on www.kofam.ch (SNCTP000004838).

Heart failure (HF) often coexists with cancer. Beyond the known cardiotoxicity of some cancer treatments, HF itself has been associated with increased cancer incidence. The 2 conditions share common risk factors, mechanisms, and interactions that can worsen patient outcomes. The bidirectional relationship between HF and cancer presents a complex interplay of factors that are not fully understood. Recent preclinical evidence suggests that HF may promote tumor growth via the release of protumorigenic factors from the injured heart, revealing HF as a potentially protumorigenic condition. Our review discusses the biological crosstalk between HF and cancer, emphasizing the impact of HF on tumor growth, with inflammation, and modulating the immune system as central mechanisms. We further explore the clinical implications of this connection and propose future research directions. Understanding the mechanistic overlap and interactions between HF and cancer could lead to new biomarkers and therapies, addressing the growing prevalence of both conditions and enhancing approaches to diagnosis, prevention, and treatment.

The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools.

Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect.

Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.

Immune system plays a crucial role in the physiological and pathological regulation of the cardiovascular system. The exploration history and milestones of immune system in cardiovascular diseases (CVDs) have evolved from the initial discovery of chronic inflammation in atherosclerosis to large-scale clinical studies confirming the importance of anti-inflammatory therapy in treating CVDs. This progress has been facilitated by advancements in various technological approaches, including multi-omics analysis (single-cell sequencing, spatial transcriptome et al.) and significant improvements in immunotherapy techniques such as chimeric antigen receptor (CAR)-T cell therapy. Both innate and adaptive immunity holds a pivotal role in CVDs, involving Toll-like receptor (TLR) signaling pathway, nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) signaling pathway, inflammasome signaling pathway, RNA and DNA sensing signaling pathway, as well as antibody-mediated and complement-dependent systems. Meanwhile, immune responses are simultaneously regulated by multi-level regulations in CVDs, including epigenetics (DNA, RNA, protein) and other key signaling pathways in CVDs, interactions among immune cells, and interactions between immune and cardiac or vascular cells. Remarkably, based on the progress in basic research on immune responses in the cardiovascular system, significant advancements have also been made in pre-clinical and clinical studies of immunotherapy. This review provides an overview of the role of immune system in the cardiovascular system, providing in-depth insights into the physiological and pathological regulation of immune responses in various CVDs, highlighting the impact of multi-level regulation of immune responses in CVDs. Finally, we also discuss pre-clinical and clinical strategies targeting the immune system and translational implications in CVDs.

Heart failure is the final outcome of most cardiovascular diseases and shares risk factors with other cardiovascular pathologies. Among these, inflammation plays a central role in disease progression and myocardial remodeling. Over the past 2 decades, numerous studies have explored immune-related mechanisms in cardiovascular disease, highlighting the importance of immune cross-talk between the heart and extra-cardiac organs, including bone marrow, spleen, liver, gut, and adipose tissue. This review examines how immune interactions among these organs contribute to heart failure pathogenesis, with a focus on clonal hematopoiesis, an age-related alteration of hematopoietic stem cells that fosters pathological bone marrow-heart communication. Additionally, we explore recent advances in the understanding of clonal hematopoiesis and its role in heart failure, emphasizing its implications for prognosis and potential therapeutic interventions. By integrating insights from immunology, metabolism, and aging, we provide a comprehensive perspective on the immunologic determinants of heart failure, paving the way for precision medicine approaches aimed at mitigating cardiovascular risk.