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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Blockade of IL1RAP (interleukin 1 receptor associated protein) was recently shown to reduce atherosclerosis in mice, but the effect on human vascular cells is largely unknown. Targeting the IL1RAP coreceptor represents a novel strategy to block the IL1RAP-dependent cytokines IL (interleukin)-1, IL-33, and IL-36. In the present study, we aimed to evaluate the role of novel antibodies targeting IL1RAP to reduce the effects of IL-1β, IL-33, or IL-36γ in human vascular cells.

Expression of IL1RAP was observed in human atherosclerotic plaques by immunohistochemistry and microarray and in endothelial cells by flow cytometry. Endothelial cells were cultured with IL-1β, IL-33, or IL-36γ cytokines with or without IL1RAP antibodies and analyzed with Olink proteomics, ELISA, Western blot, and real-time quantitative polymerase chain reaction. The functional effect of IL1RAP antibodies on endothelial cells were analyzed with adhesion and permeability assays.

Olink proteomics showed inhibition of the inflammatory proteins LIF (leukemia inhibitory factor), OPG (osteoprotegerin), CCL4 (C-C motif chemokine ligand 4), and MCP-3 (monocyte chemoattractant protein 3) by IL1RAP-blockade in endothelial cells after IL-1β stimulation. In addition, the IL1RAP antibodies inhibited IL-1β, and IL-33 induced IL-6 and IL-8 secretion. Secretion of MCP-1 (monocyte chemoattractant protein 1) was induced by IL-1β, IL-33, and IL-36γ, and subsequently was inhibited by IL1RAP antibodies. Similar effects were found on mRNA expression level. Endothelial expression of the adhesion markers ICAM1, VCAM1, and SELE were significantly reduced by IL1RAP antibodies, and neutrophil adhesion to endothelial cells induced by IL-1β and IL-33 was reduced by IL1RAP blockade. In human atherosclerotic lesions, IL1RAP expression correlated with markers of inflammation like IL6, IL8, and MCP1.

IL1RAP-targeting antibodies can reduce the expression of inflammatory cytokines and markers of adhesion in endothelial cells, which may be of importance for future putative targeted treatments against cardiovascular disease.

Patients with an autoimmune or inflammatory disease (AIID) are at increased cardiovascular risk and may benefit more from statin therapy. In the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab lowered low-density lipoprotein cholesterol levels, but not hsCRP (high-sensitivity C-reactive protein) levels, and reduced the risk of cardiovascular events.

FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with stable atherosclerosis who were taking statins. This analysis focused on the effect of evolocumab in patients with or without an AIID, defined as any autoimmune or chronic inflammatory condition. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization.

At baseline, 889 patients (3.2%) had an AIID, most commonly rheumatoid arthritis (33.7%) or psoriasis (15.6%). Median (interquartile range) low-density lipoprotein cholesterol levels were 90.0 mg/dL (79.5-105.5) and 91.5 mg/dL (79.5-108.5) in patients with or without an AIID, respectively (P=0.025), and the placebo-adjusted percent reduction with evolocumab was consistent (60.2% versus 59.0%; P=0.57). Baseline hsCRP was higher in patients with an AIID (median 2.1 versus 1.7 mg/L; P<0.001) and did not significantly change with evolocumab in either group. Compared with placebo, evolocumab reduced the rate of the primary end point by 14% in patients without an AIID (hazard ratio, 0.86 [95% CI, 0.80-0.93]) and by 42% in patients with an AIID (hazard ratio, 0.58 [95% CI, 0.38-0.89]; Pinteraction=0.066). Likewise, evolocumab reduced the key secondary end point of cardiovascular death, myocardial infarction, or stroke by 19% in patients without an AIID (hazard ratio, 0.81 [95% CI, 0.74-0.89]) and 58% in those with an AIID (hazard ratio, 0.42 [95% CI, 0.24-0.74]; Pinteraction=0.022).

Intensive lowering of low-density lipoprotein cholesterol levels with evolocumab may lead to greater relative reduction in cardiovascular events in patients with an AIID.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633.

Radiation-induced heart disease (RIHD) is a prevalent cardiovascular complication of radiation therapy, with coronary heart disease being the most common manifestation. Clinical presentations of RIHD vary and may include conduction abnormalities, ischemic heart disease, cardiomyopathy, heart failure, and valvular damage. Even low doses of radiation significantly increase the risk of cardiovascular disease, often associated with severe stenosis detected via angiography. Radiation-induced damage to the cardiac endothelium triggers inflammatory responses and oxidative stress, which contribute to the progression of atherosclerosis. This study explores how radiation activates multiple signaling pathways through the generation of reactive oxygen species, resulting in vascular endothelial damage, cellular senescence, inflammatory responses, and DNA damage. It further examines the impact of radiation on vascular integrity and tight junction proteins, leading to increased vascular permeability and infiltration by inflammatory cells. From a clinical perspective, we emphasize the challenges posed by the coexistence of tumors in many patients with RIHD, as tumors complicate the microenvironment and may have mutually reinforcing interactions with radiation-induced damage. We also discuss various therapeutic strategies, including novel approaches targeting cellular senescence and immune responses, with a focus on the potential use of navitoclax and IL-6 (interleukin-6) inhibitors to prevent irreversible cardiomyocyte fibrosis and ongoing vascular damage. In conclusion, RIHD is a multifaceted disease involving complex biological processes and signaling pathways. Early intervention and targeted therapies are crucial for improving patient outcomes. Future research should prioritize uncovering the molecular mechanisms of RIHD and developing more effective therapeutic strategies.

The LoDoCo2 (Low-Dose Colchicine 2) trial showed that colchicine reduced the risk for cardiovascular events in patients with chronic coronary syndrome. Current guidelines recommend colchicine use in selected high-risk patients. The aim of this secondary analysis was to explore the relative and absolute benefits of colchicine according to baseline risk.

The LoDoCo2 trial randomized 5522 patients to colchicine 0.5 mg or placebo. The primary end point was a composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. First, a LoDoCo2 risk score was developed by Cox regression to identify high-risk features for the primary end point. Second, the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention was applied to explore robustness of findings.

In the LoDoCo2 risk score, high-risk features were age ≥75, diabetes, and current smoker. In high-risk (≥1 high-risk feature), compared with low-risk (0 high-risk features) patients, colchicine was associated with consistent relative (high risk: hazard ratio [HR], 0.72 [95% CI, 0.56-0.94] versus low risk: HR, 0.67 [95% CI, 0.52-0.88]; P for interaction=0.73) and absolute benefits (high risk: HR, -1.33 [95% CI, -2.38 to -0.27] versus low risk: HR, -0.93 [95% CI -1.57 to -0.30] events per 100 person-years). Using the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention, consistent relative and absolute benefits were found in high-, intermediate-, and low-risk patients.

In patients with chronic coronary syndrome, the relative and absolute benefits of colchicine were consistent in those at high, intermediate, and low risk for cardiovascular events. These findings support the use of colchicine across the spectrum of baseline risk.

URL: https://www.anzctr.org.au; Unique identifier: 12614000093684.

Low-dose colchicine (0.5 mg once daily) reduces the risk of major cardiovascular events in coronary disease, but its mechanism of action is not yet fully understood. We investigated whether low-dose colchicine is associated with changes in pericoronary inflammation and plaque composition in patients with chronic coronary disease.

We performed a cross-sectional, nationwide, subanalysis of the Low-Dose Colchicine 2 Trial (LoDoCo2, n=5522). CT angiography studies were performed in 151 participants randomised to colchicine or placebo coronary after a median treatment duration of 28.2 months. Pericoronary adipose tissue (PCAT) attenuation measurements around proximal coronary artery segments and quantitative plaque analysis for the entire coronary tree were performed using artificial intelligence-enabled plaque analysis software.

Median PCAT attenuation was not significantly different between the two groups (-79.5 Hounsfield units (HU) for colchicine versus -78.7 HU for placebo, p=0.236). Participants assigned to colchicine had a higher volume (169.6 mm3 vs 113.1 mm3, p=0.041) and burden (9.6% vs 7.0%, p=0.035) of calcified plaque, and higher volume of dense calcified plaque (192.8 mm3 vs 144.3 mm3, p=0.048) compared with placebo, independent of statin therapy. Colchicine treatment was associated with a lower burden of low-attenuation plaque in participants on a low-intensity statin, but not in those on a high-intensity statin (pinteraction=0.037).

Pericoronary inflammation did not differ among participants who received low-dose colchicine compared with placebo. Low-dose colchicine was associated with a higher volume of calcified plaque, particularly dense calcified plaque, which is considered a feature of plaque stability.

Traditional cardiovascular risk factors, combined with persistent systemic inflammation, contribute to the increased prevalence of atherosclerotic cardiovascular disease (ASCVD) in people with HIV (PWH). This review highlights key findings from the REPRIEVE trial on statin-based primary prevention of major adverse cardiovascular events in PWH. It explores HIV-specific immune mechanisms contributing to residual cardiovascular risk.

In REPRIEVE, statin therapy used for primary prevention of major adverse cardiovascular events in PWH decreased the plasma lipoprotein-associated phospholipase A2, oxidized low-density lipoprotein, and high-sensitivity C-reactive protein (hs-CRP). However, several inflammatory markers including soluble CD14 (sCD14), sCD163, interleukin (IL)-1β, interleukin (IL)-6, IL-10, and caspase 1 did not change. The HIV reservoir, dysfunctional CD4+ T cells, immunoglobulin G N-glycans, antiapolipoprotein A1 autoantibodies, trained immunity, and clonal hematopoiesis of indeterminate potential may contribute to residual inflammation.

Despite antiretroviral and statin therapy, residual ASCVD risk in PWH underscores the need for targeted interventions. Anti-inflammatory therapies, including IL-6 and IL-1β inhibitors, CCR5 antagonists (e.g., maraviroc, cenicriviroc mesylate), and immunomodulatory agents like methotrexate and colchicine, are being explored. Understanding HIV-driven immune dysregulation may lead to novel strategies to mitigate cardiovascular risk in this population.

For more than a century, hypercholesterolemia has been linked to atherosclerotic cardiovascular disease. Notably, this metabolic condition has also been pointed out as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). Oxidative stress seems to be the connective factor between hypercholesterolemia and cardio and neurological disorders. By disturbing redox homeostasis, hypercholesterolemia impairs nitric oxide (NO) availability, an essential vasoprotective element, and jeopardizes endothelial function and selective permeability. The central nervous system (CNS) is partially protected from peripheral insults due to an arrangement between endothelial cells, astrocytes, microglia, and pericytes that form the blood-brain barrier (BBB). The endothelial dysfunction related to hypercholesterolemia increases the risk of developing cardiovascular diseases and also initiates BBB breakdown, which is a cause of brain damage characterized by neuroinflammation, oxidative stress, mitochondrial dysfunction, and, ultimately, neuronal and synaptic impairment. In this regard, we reviewed the mechanisms by which hypercholesterolemia-induced oxidative stress affects peripheral vessels, BBB, and leads to memory deficits. Finally, we suggest oxidative stress as the missing link between hypercholesterolemia and dementia.

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.

The aim of this study was to evaluate and compare the usefulness of the C-reactive protein (CRP)-triglyceride glucose (TyG) index (CTI) and other insulin resistance (IR) or inflammatory indexes for predicting recurrent cardiovascular events in percutaneous coronary intervention (PCI)-treated patients. In addition, the mediating effects of systemic inflammation, represented by high-sensitive CRP (hs-CRP), on TyG index-associated adverse cardiovascular events across different subgroups were also evaluated.

The formula for calculating the CTI was 0.412 × ln [high-sensitivity CRP (mg/L)] + ln [triglyceride (mg/dl) × fasting glucose (mg/dl)/2]. The primary endpoint was defined as the incidence of major adverse cerebrovascular and cardiovascular events (MACCEs), including cardiovascular death, nonfatal acute myocardial infarction (AMI), nonfatal ischemic stroke and repeat coronary revascularization.

Among the 2383 PCI-treated patients, 413 experienced MACCEs during a median of 34 months follow-up. Correlation analysis showed CTI was significantly associated with cardiometabolic factors. The CTI was the strongest predictor for MACCEs (adjusted HR 1.85, 95% CI 1.44-2.38) among the inflammatory and IR indicators. CTI had an incremental effect on the predictive ability of the prognostic model for MACCEs (NRI: 0.220, p < 0.001; IDI: 0.009, p < 0.001). Subgroup analysis revealed that the prognostic value of the CTI remained significant across all subgroups (all p < 0.05) whereas the predictive abilities of other IR or inflammatory indicators were more or less influenced by the metabolic abnormalities. Finally, mediation analysis revealed that the effects of systemic inflammation on TyG index-associated MACCEs were more prominent in patients with metabolic disorders.

CTI was a practical indicator for evaluating cardiometabolic diseases. Among the IR and inflammatory indicators, CTI was the most promising index for predicting recurrent cardiovascular risks in PCI-treated patients. TyG index-associated cardiovascular risks were partially mediated by systemic inflammation in patients with metabolic abnormalities.

Acute coronary syndrome (ACS) is a global leading cause of morbidity, with residual inflammation contributing to recurrent events. Colchicine has been proposed as an adjunct therapy, but its efficacy remains uncertain.

We performed a systematic review and meta-analysis. PubMed, Embase and Cochrane databases were searched for randomised controlled trials (RCTs) data comparing colchicine versus placebo in ACS. Risk ratio (RR) and mean difference with 95% CIs were computed for binary and continuous outcomes, respectively. Primary outcomes were adverse cardiovascular events (ACEs), mortality and safety. Random-effects models were used for pooled estimates.

Seventeen RCTs comprising 14 794 patients were included, of whom 7390 (50%) were randomised to colchicine. The mean patient age across the studies ranged from 54 to 63 years, in a follow-up period ranging from 5 days to 12 months. Colchicine reduced the incidence of recurrent ACS (RR 0.41, 95% CI 0.19 to 0.92; p=0.03; I²=55%) and unstable angina (RR 0.27, 95% CI 0.11 to 0.63; p<0.01; I²=0%). No meaningful differences were observed in all-cause mortality (RR 0.95, 95% CI 0.79 to 1.14; I²=12%), cardiovascular death (RR 1.03, 95% CI 0.82 to 1.30; I²=0%) or ACE (RR 0.77, 95% CI 0.59 to 1.01; p=0.05; I²=58%). Subgroup analyses suggested a dose-dependent effect, with 0.5 mg/day potentially reducing ACE (RR 0.63, 95% CI 0.45 to 0.88; I²=41%), but higher doses increasing gastrointestinal symptoms.

Low-dose colchicine may reduce recurrent ischaemic events in ACS, but evidence remains uncertain due to heterogeneity and limited long-term data. Safety and efficacy in women and optimal dosing require further investigation.

CRD42024627348.

Research into the role of chronic sterile inflammation (i.e. a prolonged inflammatory state not caused by an infectious agent), in vascular disease progression has continued to grow over the last few decades. DAMPs have a critical role in this research due to their ability to link stress-causing cardiovascular risk factors to inflammatory phenotypes seen in vascular disease. In this mini-review, we will briefly summarize the DAMPs and receptor signaling pathways that have been extensively studied in the context of vascular disease, including TLRs, RAGE, cGAS-STING, and the NLRP3 inflammasome. In particular, we will discuss how these pathways can promote the release of pro-inflammatory cytokines and chemokines as well as vascular remodeling. Next, we will summarize the results of studies which have linked the various pro-inflammatory effects of DAMPs with the phenotypes in the context of vascular diseases including atherosclerosis, fibrosis, aneurysm, ischemia, and hypertension. Finally, we will discuss some pre-clinical and clinical trials that have targeted DAMPs, their receptors, or the products of their signaling pathways, and discuss the outlook and future directions for the field at large.

Recent studies suggest that vascular senescence and its associated inflammation fuel the inflammaging to favor atherogenesis; whether these pathways can be therapeutically targeted in coronary artery disease (CAD) patients remains unknown. In a randomized, double-blind trial, 97 patients (78 men) undergoing coronary artery bypass graft surgery were treated with either quercetin (500 mg twice daily, 47 patients) or placebo (50 patients) for two days pre-surgery through hospital discharge. Primary outcomes were reduced inflammation and improved endothelial function ex vivo. Exploratory analyses included plasma proteomics and single-nuclei RNA sequencing of internal thoracic artery (ITA) samples. Quercetin treatment showed a trend toward reduced C-reactive protein at discharge (p = 0.073) and differentially modulated circulating inflammatory protein expression between men and women, with a pro-inflammatory effect of quercetin in females. Endothelial acetylcholine-induced relaxation improved significantly with quercetin (p = 0.049), with effects in men (p = 0.043) but not in women (p = 0.852). ITA transcriptomics revealed the overexpression of senescence and inflammaging pathways in male vascular cells, which quercetin reversed. In female cells, quercetin had minimal endothelial benefit and increased inflammaging in fibroblasts. In male cells, a candidate target of quercetin involves interactions between the receptor PLAUR and its ligands PLAU and SERPINE1. Post-operative atrial fibrillation incidence was significantly lower with quercetin, representing 4% of the patients compared to 18% in the placebo group (p = 0.033). In conclusion, short-term quercetin treatment effectively targeted vascular senescence in male CAD patients, improving inflammatory and functional outcomes. However, these benefits were not observed in female patients. Trial Registration: https://clinicaltrials.gov, NCT04907253.

In recent years, the efficacy of various physical exercise programs in enhancing functional fitness among frail older adults has gained recognition. However, limited research has concurrently explored the long-term effects of exercise on brain health, stress biomarkers, and mental well-being. This study aimed to investigate the impact of two distinct chair-based exercise programs on salivary stress hormones and psychological well-being in frail older women over a 28-week period.

A total of 140 individuals participated in the enrollment phase, with 84 eligible participants randomly assigned to three groups. Following the intervention, data from 60 participants were analyzed across the multicomponent exercise (MCE, n = 23), elastic band muscle-strength exercise (ESE, n=19), and non-exercise control (CG n=18) groups. Salivary biomarkers of alpha-amylase (α-AMY) Cortisol (COR), alpha-amylase/cortisol ratio, psychological indicators and physical frailty (PF) and functional fitness were assessed pre- and post-intervention.

Salivary COR levels exhibited a significant time × group interaction, with a moderate increase in MCE, a small decrease in ESE, and a substantial increase in CGne. Salivary α-AMY levels varied significantly over time and by group, with a small decrease in both exercise groups and a moderate increase in CGne. The α-AMY /COR ratio also displayed a significant interaction effect. Additionally, significant improvements were observed in PF compound scores, general self-efficacy, attitudes toward aging, and reductions in perceived stress and depressive symptoms (p < 0.05).

Notably, the MCE program demonstrated greater benefits than ESE. The observed associations between changes in α-AMY levels, mental well-being, and functional fitness indicators contribute novel evidence on the psychophysiological adaptations to long-term exercise. Importantly, reductions in PF scores correlated with improvements in self-efficacy, attitudes toward aging, and handgrip strength, reinforcing the link between functional fitness, stress regulation, and psychological well-being. These findings emphasize the need for tailored exercise interventions to enhance both physiological resilience and mental health in frail older populations.

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 NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a megadalton complex implicated in numerous inflammation-driven diseases including COVID-19, Alzheimer's disease, and gout. Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available. MCC950, a direct NLRP3 inhibitor, showed promise but exhibited off-target effects. Recent research has focused on optimizing the sulfonylurea-based MCC950 scaffold by leveraging recent structural and medicinal chemistry insights into the NLRP3 nucleotide-binding and oligomerization (NACHT) domain to improve solubility and clinical efficacy. In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. This comprehensive review aims to elucidate the intricate mechanisms by which inflammation contributes to the development and progression of HF. The review synthesizes current research on the involvement of both innate and adaptive immune responses in HF, highlighting the roles of cytokines, chemokines, and other inflammatory mediators. Recent studies have demonstrated that chronic inflammation, driven by factors such as oxidative stress, neurohormonal activation, and metabolic disturbances, leads to adverse cardiac remodeling and impaired myocardial function. The review explores how systemic inflammation, characterized by elevated levels of inflammatory biomarkers like C-reactive protein (CRP) and interleukin-6 (IL-6), correlates with HF severity and outcomes. Additionally, it discusses the impact of comorbid conditions such as diabetes, obesity, and hypertension on inflammatory pathways and HF risk. The review also delves into the therapeutic implications of targeting inflammation in HF. Despite mixed results from early clinical trials, emerging evidence suggests that anti-inflammatory therapies offer benefits in specific HF phenotypes. The potential of novel therapeutic strategies, including the use of biologics and small molecule inhibitors, is examined in the context of their ability to modulate inflammatory responses and improve clinical outcomes.