Recreational drugs affect the cardiovascular system through distinct mechanisms; however, data regarding their cardiovascular impact in the emergency department setting is limited. This study aimed to assess the incidence of cardiovascular effects following recreational drug use in presentations to the emergency department, identify the main drug groups involved, and compare cases with and without cardiovascular effects. Data were extracted from the European Drug Emergency Network (Euro-DEN Plus) dataset from October 2013 to December 2021. Recreational drugs were categorised into ten main drug groups: opioids, cocaine, crack cocaine, cannabis, 3,4-methylenedioxymethamfetamine, amfetamine-type stimulants, gamma-hydroxybutyrate and gamma-butyrolactone, hallucinogens, benzodiazepines, and ketamine. Among 59,571 presentations, 13,905 (23.3%) involved cardiovascular effects. Cocaine (OR 3.19, 95% CI 2.99-3.39) and 3,4 methylenedioxymethamphetamine (OR 1.18, 95% CI 1.13-1.23) showed the strongest associations with cardiovascular features, including chest pain, palpitations, hypertension, and arrhythmias. Opioids (OR 0.35, 95% CI 0.31-0.38) and benzodiazepines (OR 0.38, 95% CI 0.32-0.44) were associated with less frequent cardiovascular features. Patients with cardiovascular features exhibited higher median values for temperature, heart rate, blood pressure, and respiratory rate (p <0.001). Cardiovascular features were associated with an increased risk of intubation (OR 1.91, 95% CI 1.70-2.15), critical care admission (OR 2.18, 95% CI 2.00-2.38), and mortality (OR 15.8, 95% CI 7.36-33.9). Cardiovascular effects were common in acute recreational drug toxicity. Cocaine and amfetamine-type stimulants increased the risk of chest pain and arrhythmias, with chest pain being a key indicator of acute coronary syndrome. Cardiovascular effects were more frequently observed with cocaine than with crack cocaine. Cannabis was positively associated with palpitations but not arrhythmias. Gamma-hydroxybutyrate and gamma-butyrolactone, opioids, and benzodiazepines were linked to hypotension. The presence of cardiovascular effects was associated with worse outcomes, underscoring the need for thorough cardiac assessment. Cardiovascular effects were present in almost a quarter of emergency department presentations with acute recreational drug toxicity, particularly involving cocaine and 3,4 methylenedioxymethamphetamine.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with significant attention focused on the development of therapeutic drugs and research into pathogenic mechanisms. In the real world, cardiotoxicity induced by multiple factors commonly exists and is closely associated with cardiovascular diseases. Traditional toxicity testing models (such as animal experiments and two-dimensional cell cultures) have limited clinical translation value due to species differences, inability to simulate the complex microenvironment of the human body, and cellular interactions. Cardiac organoids, as an emerging three-dimensional (3D) culture platform, possess 3D structure, multicellular composition, organ-specific functions, and self-organizing capabilities, which can highly mimic the physiological and pathological characteristics of the heart, providing a more precise humanized model for the study of cardiovascular disease mechanisms, drug development, and toxicity assessment. This paper systematically reviews the construction strategies of cardiac organoids and their application progress in toxicology: Firstly, it explores the construction standards and technical optimization of cardiac organoids, focusing on human-engineered heart tissue (hEHT) models and various cardiac organoid models that mimic the human heart, with particular attention to their unique characteristics, utility, and limitations. Secondly, through bibliometric analysis using CiteSpace, it reveals research hotspots and trends in cardiac organoid applications for toxicology, specifically by extracting collaboration networks, conducting co-citation analysis, and co-occurrence analysis. Finally, it summarizes specific applications of cardiac organoids in toxicology, including drug toxicity assessment, environmental pollutant toxicity evaluation, cardiac developmental toxicity studies, disease model construction, and multi-organ cascade studies for systemic toxicity assessment.
Chronic alcohol consumption induces multisystem dysfunction, including cardiovascular instability, hematological alterations, and oxidative stress imbalance. However, the extent of short-term recovery following structured detoxification remains incompletely characterized. To evaluate the short-term effects of a standardized inpatient alcohol detoxification protocol on cardiovascular, hematological, and oxidative stress biomarkers. A prospective observational before-and-after cohort study was conducted on 75 male participants, including 50 patients with alcohol use disorder and 25 healthy controls. Patients underwent a 21-day inpatient detoxification program comprising pharmacological stabilization and nutritional rehabilitation. Clinical and biochemical parameters-including body mass index, vital signs, lipid profile, complete blood counts, troponin-I, and oxidative stress markers (TBARS, glutathione peroxidase, and catalase)-were assessed at baseline and post-treatment. Compared to healthy controls, treatment-naïve patients with alcohol use disorder (AUD) exhibited significantly elevated baseline levels of lymphocytes, total cholesterol, low-density lipoprotein (LDL), thiobarbituric acid reactive substances (TBARS), and catalase (CAT), alongside significantly lower heart rate (HR), systolic blood pressure (SBP), neutrophil-to-lymphocyte ratio (NLR), high-density lipoprotein (HDL), and glutathione peroxidase (GPx). Baseline anthropometric, vital, hematological, and metabolic markers-including BMI, diastolic blood pressure (DBP), hemoglobin (Hb), platelets, total white blood cell count (WBCs), cardiac troponin-I (cTnI), and triglycerides-showed no statistically significant differences. Following a 21-day inpatient detoxification protocol, post-treatment assessments revealed significant increases in red blood cell parameters (RBCs, Hb, Hct), neutrophils, lymphocytes, NLR, and HDL. Conversely, standard detoxification induced significant reductions in cardiovascular, lipid, and oxidative stress indices, specifically HR, SBP, mean corpuscular volume (MCV), total WBCs, cTnI, total cholesterol, triglycerides, TBARS, and CAT. No significant post-treatment alterations were observed in BMI, DBP, platelet counts, LDL, or GPx. Short-term alcohol detoxification leads to partial recovery of cardiovascular and hematological parameters, while oxidative stress markers show limited normalization within the 21-day period. These findings highlight differential recovery patterns across biological systems following early abstinence.
Idiopathic pulmonary arterial hypertension (PAH) is a progressive cardiovascular disorder with high mortality. Although both genetic and environmental factors are implicated in its pathogenesis, the underlying mechanisms remain unclear. We integrated transcriptomic data from PAH lung tissue, GWAS summary statistics, and QTL data for DNA methylation, gene expression, and plasma protein. Core dysregulated genes were first identified via differential expression and protein-protein interaction network analysis. Using summary-data-based Mendelian randomization (SMR), we systematically evaluated potential potential genetic associations between methylation, expression, or protein levels of candidate genes and PAH risk, with the HEIDI test to distinguish causality from pleiotropy. Key findings were validated by examining gene expression trends in two independent cohorts. Finally, reverse network toxicology was applied: environmental pollutants targeting identified genes were screened using the CTD, their binding potential assessed via molecular docking, and effects of a candidate pollutant on gene expression and cell proliferation validated in vitro in human pulmonary artery smooth muscle cells (HPASMCs). We identified 254 differentially expressed genes in PAH. Among these, TAGLN2 exhibited a significant positive association with PAH risk at three molecular levels-DNA methylation, gene expression, and plasma protein, suggesting a pathogenic role. Specifically, increased TAGLN2 protein abundance (HR = 9.00, 95% CI: 1.52-53.16) and gene expression levels (HR = 9.00, 95% CI: 1.52-53.16) were associated with higher PAH risk, while its methylation sites (e.g., cg13892570, cg16107628) showed a negative association. Validation in two independent cohorts confirmed that TAGLN2 expression was upregulated in the lung tissue of PAH patients. Reverse toxicology predicted eight environmental pollutants as potential TAGLN2-targeting agents, including PFOS, dibutyl phthalate, bisphenols, and benzo[a]pyrene. Molecular docking indicated that all these compounds could bind stably to the TAGLN2 protein (binding free energy < -5.0 kcal/mol), with PFOS exhibiting the strongest binding affinity (-8.9 kcal/mol). In vitro experiments showed that PFOS upregulated TAGLN2 mRNA expression in HPASMCs and promoted cell proliferation in a dose-dependent manner, providing preliminary correlative evidence. This study prioritizes TAGLN2 as a genetically associated candidate gene for PAH and identifies environmental pollutants that may target TAGLN2. While the in vitro data show that PFOS upregulates TAGLN2 expression and promotes HPASMC proliferation, functional perturbation experiments are needed to establish a mechanistic requirement for TAGLN2. These findings provide hypothesis-generating insights into potential gene-environment interactions in PAH.
The unique physicochemical properties of nanoparticles (NPs) have facilitated the development of targeted therapies for cardiovascular diseases (CVDs). According to World Health Organization estimates, CVDs are the predominant contributors to global mortality, accounting for approximately 17.9 million deaths annually. Conventional treatments, including pharmacological interventions and surgical procedures, face significant barriers such as systemic toxicity due to non-targeted delivery, incomplete efficacy, and high financial burdens. Nanoscale innovations address these limitations through mechanisms such as targeted drug delivery and controlled release. Despite these advancements, concerns regarding NPs-induced cardiotoxicity remain unresolved. As nanomedicine advances rapidly, understanding NP functions within the cardiovascular system is essential for optimizing therapeutic outcomes in parallel to minimize unintended risks. Metal-based NPs, including gold, silver, and iron oxide, have demonstrated promising applications in cardiovascular imaging, regenerative therapy, and drug delivery; however, emerging evidence indicates their potential to induce oxidative stress, inflammatory responses, and endothelial dysfunction, contributing to atherosclerosis, myocardial injury, and arrhythmias. Inhaled and intravenously administered NPs exhibit dose-dependent toxicities that influence mitochondrial function and calcium homeostasis within cardiomyocytes. This review comprehensively analyzes in vitro and in vivo studies and notable clinical trials such as the NANOM-FIM trial. Furthermore, we discuss the role of specific antioxidants in cardioprotection and mitigating NPs-induced cardiotoxicity.
Epidemiological and experimental studies have linked legacy and emerging PFAS to adverse cardiovascular outcomes, yet most evidence remains observational and is susceptible to confounding, measurement error, and reverse causation. This study used European-ancestry GWAS data and two-sample Mendelian randomization to assess potential causal associations between PFOA or PFOS exposure and five cardiovascular diseases. For significant MR findings, network toxicology was integrated with transcriptomic data to identify candidate targets and pathways, followed by machine learning-based prioritization. Immune cell infiltration, single-cell transcriptomic analysis, molecular docking, and molecular dynamics simulation were further applied to explore immune mechanisms and pollutant-protein interactions. Genetically predicted PFOS exposure was associated with an increased risk of peripheral artery disease. Enrichment analysis implicated PPAR and PI3K-Akt signaling pathways, while machine learning based on 129 overlapping genes identified HMOX1, KDR, MMP9, and PPARG as key targets. Immune infiltration and single-cell analyses indicated remodeling of the PAD immune microenvironment, with HMOX1 mainly enriched in macrophages. Virtual knockout highlighted APC-related MHC II antigen presentation, and docking and dynamics simulations supported stable PFOS-HMOX1 binding. These findings suggest a potential PFOS-PAD association and provide candidate biomarkers for further validation.
Adolescence is a developmental stage marked by dynamic interactions between diet, the gut microbiome and endocrine maturation, creating a physiological environment in which early metabolic disturbances can rapidly translate into long-term cardiovascular vulnerability. This narrative review summarises the latest research on the diet-microbiome-hormone axis in adolescents, focusing on the metabolic pathways through which microbial metabolites influence host physiology. Short-chain fatty acids (SCFAs), microbially transformed bile acids and postbiotic signalling molecules regulate enteroendocrine communication, insulin sensitivity, vascular function and inflammatory tone, thereby linking dietary exposures to early cardiometabolic alterations. Dysbiosis, driven by ultra-processed dietary patterns, low fibre intake and reduced microbial diversity, promotes metabolic endotoxemia, neuroendocrine imbalance and endothelial impairment, all of which are recognised as early indicators of cardiovascular disease. A distinctive contribution of this review is the integration of PF into the adolescent cardiometabolic framework. This emerging biotechnological process enables the controlled production of structurally defined bioactive compounds, including angiotensin-converting enzyme (ACE) inhibitory peptides, targeted prebiotic oligosaccharides, fermentable substrates that promote SCFA formation, microbially derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), phytosterols and purified postbiotics. These compounds modulate several regulatory pathways, such as the renin-angiotensin-aldosterone system, lipid and bile acid metabolism, gut barrier stability, inflammatory signalling and endocrine axes involving glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, insulin sensitivity and growth hormone/insulin-like growth factor-1 (GH/IGF-1) dynamics. By situating precision fermentation within the broader context of adolescent metabolic susceptibility, this review highlights its potential to support microbiome resilience, stabilise hormonal regulation and mitigate early cardiovascular risk. However, further adolescent-specific clinical trials and long-term safety assessments are required to translate these advances into effective public health strategies.
Depression is a major global public health burden, and environmental pollutants are increasingly associated with depressive symptoms. Volatile organic compounds (VOCs) are ubiquitous environmental contaminants with known neurotoxic potential; however, their associations with depressive symptoms, particularly in metabolically vulnerable populations such as those with cardiovascular-kidney-metabolic (CKM) syndrome, remain insufficiently characterized. We conducted a population-based study of adults with CKM stages 0-3 using data from NHANES 2011-2018, assessing associations between urinary levels of 16 VOC metabolites and PHQ-9-defined depressive symptoms using multivariable logistic regression, dose-response modeling, and mixture analyses. Machine learning identified key exposures, network toxicology revealed shared molecular targets and pathways, single-cell RNA sequencing characterized cell-type-specific expression and functional states, and molecular docking assessed interactions between prioritized mVOCs and protein targets. Higher urinary levels of CYMA, MHBMA3, and HMPMA were significantly associated with increased odds of depressive symptoms after full adjustment, with approximately linear or nonlinear dose-response relationships. Mixture analysis indicated that these metabolites were the main contributors to the joint VOC exposure effect. Network toxicology identified enrichment of depression-related targets in neuronal signaling, synaptic transmission, and immune regulation pathways. Exploratory analysis of public scRNA-seq datasets suggested higher PIK3R1 expression in PBMC CD8+ T cells from depression-related samples and indicated altered immune-related transcriptional programs. Molecular docking suggested plausible binding interactions between the prioritized VOCs and PIK3R1. Higher urinary VOC metabolite levels were associated with higher odds of PHQ-9-defined depressive symptoms among adults with CKM stages 0-3.In silico multi-omics analyses suggested potential involvement of PI3K/AKT-related neuroimmune pathways.
Cocoa shell extract (CSE; rich in antioxidant compounds) administered to adult hypertensive rats exposed to fetal undernutrition (MUN) reduces blood pressure, improving cardiovascular alterations. We aimed to explore lactation as a reprogramming window, evaluating the long-term effects of CSE supplementation during this period. MUN and control (C) dams were given 250 mg/kg/day CSE (5 days/week) or vehicle (VEH) in gelatine throughout lactation. Blood pressure (tail-cuff plethysmography), heart (echocardiography) and mesenteric resistance artery (MRA) function (wire myography) and structure (pressure myography, confocal microscopy) were studied in 8-month-old offspring. MUN-VEH rats had significantly higher blood pressure and reduced MRA internal diameter compared with C-VEH counterparts. MUN-VEH males also had smaller left ventricular mass index, acetylcholine, sodium nitroprusside relaxations and increased stiffness, whereas MUN-VEH females had elevated maximal noradrenaline-evoked contractions. CSE administration led to lower body weight in most groups and a lower blood pressure in MUN-CSE, but not C-CSE rats, compared with non-treated counterparts. Supplementation reduced left ventricular mass index, heart rate and ejection fraction in all groups and worsened MRA acetylcholine-mediated vasodilatation in MUN-CSE females and C-CSE males and females. CSE induced medial layer hypertrophy in all groups; it increased internal diameter only in MUN-CSE rats and it elevated wall-to-lumen ratio in C-CSE rats. In conclusion, although CSE supplementation during lactation prevented the development of hypertension in MUN rats, the induced cardiovascular functional and structural alterations, particularly in control offspring, suggest detrimental effects of CSE bioactive components, at least at the dose used. This study highlights the need for caution when administering supplements during lactation.
Body mass index (BMI) is commonly used to estimate obesity-related risk, but it does not reflect fat distribution. A Body Shape Index (ABSI), which captures central adiposity independently of BMI, may offer better prognostic value. We compared ABSI and BMI as predictors of all-cause and cardiovascular (CV) mortality in a general rural population. This prospective analysis included 820 participants from the ENAH (Endemic Nephropathy in Croatia - Epidemiology, Diagnostics and Etiopathogenesis) cohort with complete baseline anthropometric data. BMI and ABSI were calculated at baseline and expressed as z-scores. Participants were followed for a median of 9.7 years. Associations with all-cause mortality, CV mortality, and a composite non-fatal outcome were examined using multivariable Cox regression. Discriminative ability was assessed by receiver operating characteristic analysis. Higher ABSI was independently associated with increased all-cause mortality (hazard ratio per 1-SD increase 1.15, 95% confidence interval 1.01-1.32) and CV mortality (1.27, 1.04-1.55), whereas BMI showed no significant association with either outcome. Mortality risk increased across ABSI tertiles but not BMI tertiles. ABSI demonstrated better discrimination for all-cause and CV mortality than BMI, while neither index predicted non-fatal outcomes. ABSI outperformed BMI in predicting all-cause and CV mortality. Measures of central adiposity such as ABSI may improve mortality risk stratification beyond BMI alone.
Saururus chinensis (Lour.) Baill. is a traditional medicinal herb widely used in East Asia, with a long history of use in traditional Chinese medicine and traditional Korean medicine. It is traditionally used to clear heat, detoxify, promote diuresis, and reduce swelling, particularly for damp-heat-related disorders. Given its long-standing ethnomedicinal use, S. chinensis has considerable potential for further development. Although studies on S. chinensis have increased rapidly, no comprehensive systematic review dedicated to this species is available. This review summarizes its botany, traditional uses, phytochemistry, pharmacology, quality control, pharmacokinetics, and toxicity, with the aim of evaluating its therapeutic potential and identifying current research gaps. Relevant literature is systematically retrieved from PubMed, Web of Science, CNKI, and other major databases. The collected studies are screened, organized, and comprehensively analyzed. A total of 232 compounds have been identified from S. chinensis, with lignans as the predominant class of constituents. Available studies indicate that S. chinensis exhibits antitumor, anti-inflammatory, cardiovascular-protective, neuroprotective, multiorgan-protective, metabolic-regulatory, antioxidant, antimicrobial, skin-protective, anti-asthmatic, anti-allergic, and bone-protective activities. However, several issues remain, including unclear toxic mechanisms, the lack of a well-defined safe dosage range, insufficient understanding of synergistic effects, low bioavailability, and incomplete quality control. S. chinensis shows considerable potential for further development. Future studies should address these issues to support the safe, effective, and standardized development and application of this medicinal plant.
Dyslipidemia poses a significant challenge to public health worldwide. Many researchers have suggested that nutritional and environmental factors contribute to dyslipidemia. This study aimed to examine the relationship between serum levels of selected essential and non-essential elements, calcium (Ca), cobalt (Co), magnesium (Mg), potassium (K), lithium (Li), boron (B), and aluminum (Al) and dyslipidemia. Additionally, we aimed to explore the interactions between these elements in various mixtures using the Bayesian Kernel Machine Regression (BKMR) model. This cross-sectional analytical study was conducted among the Kurdish population in western Iran, using data from the Ravansar non-communicable diseases (RaNCD) study. A total of 224 participants aged between 35 and 65 years were included. Data collection included demographic information and blood samples, which were analyzed for selected elements using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). We applied logistic regression and BKMR models to analyze the effects of the studied serum elements on dyslipidemia. Among 224 participants, dyslipidemia prevalence was 54.9%, higher in cardiovascular disease (CVD) patients (61.8%) than in non-CVDs (49.2%). Individuals with dyslipidemia had significantly higher age, body mass index (BMI), and blood pressure, while no significant differences were found in sex, residence, marital status, or education level. The logistic regression analysis, after adjusting for confounding factors in the CVD subgroup, indicated that higher serum Ca concentrations were associated with higher odds of dyslipidemia compared with lower concentrations. In contrast, higher serum Co and Mg concentrations were associated with lower odds of dyslipidemia. The BKMR model revealed that the serum levels of B in all subjects, and K, Co, and Ca in the CVD group, as well as B and Co in the non-CVD group, exhibited the highest posterior inclusion probability (PIP) values. This study suggests a potential association between serum levels of Ca, Co, Mg, and dyslipidemia in a representative sample of patients with CVD.
Per- and polyfluoroalkyl substances (PFAS) are persistent, chemically stable compounds widely used in daily life. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS) were identified as the most relevant PFAS due to their prevalence and toxicity. This study aimed to investigate the immunotoxic mechanisms of a mixture of these PFAS using an in silico approach. Comparative Toxicogenomic Database (CTD), GeneMANIA, CytoHubba (Cytoscape), ToppGene Suite, and Metascape were used for the analysis. A total of 65 immune-related genes were identified as common to all four PFAS, with IFNG, TNF, IL1B, IL6, TYK2, CD3E, CASP8, VAV1, ARHGAP4, and CARD11 emerging as key hub genes. CTD phenotype analysis indicated immune dysregulation, with decreased humoral and adaptive immune responses in humans and tissue-specific modulation of B- and T-cell activity in mice, while no immune-related phenotypes were observed for PFNA. Network analysis identified functional modules associated with apoptotic and immune signaling, endothelial cell migration and angiogenesis, and shared inflammatory and viral response pathways. Disease enrichment analysis associated PFAS with autoimmune disorders (rheumatoid arthritis, asthma), metabolic conditions, and cardiovascular diseases (experimental diabetes, hypertensive disease). These results highlight PFAS involvement in immune modulation, cytokine signaling, and disease susceptibility.
Benzo[a]pyrene (BaP), an air pollution-related polycyclic aromatic hydrocarbon, may intersect with molecular pathways relevant to atrial fibrillation (AF), but this relationship remains unclear. To examine whether predicted BaP targets overlap with molecular and cellular remodeling features in human AF-related atrial datasets. Five AF microarray datasets and one single-cell RNA sequencing (scRNA-seq) dataset were analyzed. Differential expression and weighted gene co-expression network analysis (WGCNA) defined AF-associated key genes directly observed from human AF transcriptomic datasets. BaP predicted targets were computationally obtained using ChEMBL, Similarity Ensemble Approach (SEA), and PharmMapper; their overlap with AF-associated key genes defined inferred BaP-AF candidate targets for Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Machine learning (ML) with SHapley Additive exPlanations (SHAP) prioritized hub genes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT), docking, and single-cell analyses assessed immune patterns, structural plausibility, and cellular context. Eighteen inferred BaP-AF candidate targets were identified by overlapping AF-associated key genes with BaP predicted targets, and these candidates were enriched in oxidative stress/inflammation and transforming growth factor-beta (TGF-β)-related remodeling pathways. Elastic Net yielded a final hub-gene signature (PPP3CA, ERBB4, PSAP, LAMP1, PPARA, HSP90AB1, TGFBR1, KCNA5). AF exhibited increased neutrophils and reduced M2 macrophages/T follicular helper (Tfh) cells. Single-cell analyses of AF-related human atrial tissue localized the hub genes to major cell populations and revealed AF-associated immune expansion and fibroblast-centered TGF-β signaling, dominated by TGFB1-(TGFBR1 + TGFBR2), rather than directly measuring BaP-induced single-cell remodeling.scTenifoldKnk-based TGFBR1 virtual knockout highlighted perturbations (ABCA8, CD9, IFI44L, BGN). These findings nominate a testable hypothesis that BaP-related target perturbations may intersect with TGFBR1-associated fibroblast remodeling in AF. Future studies should evaluate this hypothesis in exposure-relevant atrial cell models through controlled BaP exposure and TGFBR1 gain- or loss-of-function experiments, followed by in vivo validation of fibroblast activation and atrial remodeling.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE), heart failure, and mortality through undetermined mechanisms independent of glycemic control. This review examines emerging evidence that GLP-1RAs overcome vascular regenerative cell exhaustion (VRCE), a pathological depletion of bone marrow-derived progenitor cells that mediate vessel repair. VRCE, the progressive loss of circulating progenitor cells that mediate vessel regeneration, has recently emerged as an underappreciated driver of MACE risk in individuals living with type 2 diabetes (T2D), obesity or atherosclerotic cardiovascular disease. In a recent randomized translational trial of semaglutide vs. usual care, SEMA-VR CardioLink-15 provided the direct evidence that 6-month semaglutide administration could reverse VRCE profile associated with longstanding cardiometabolic disease (34.8% increase in VR myeloid progenitor cells, 66.2% expansion of endothelial precursor cells). Semaglutide additionally reduced circulating granulocyte content and suppressed pro-inflammatory TNF and interleukin family cytokines in sera. GLP-1RAs can restore bone marrow progenitor cell output towards a more vessel regenerative profile. Reversal of VRCE may partially explain early event curve separation in cardiovascular outcome trials with multiple GLP-1RAs. Therefore, circulating VR cell content could serve as a measure of compromised vascular regenerative capacity and elevated cardiovascular disease risk.
Phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling and cardiovascular disease. Recent lineage-tracing and single-cell transcriptomic studies have identified secreted phosphoprotein 1 (SPP1) as a prominent marker associated with disease-associated VSMC states, particularly those linked to fibrotic remodeling and vascular calcification. However, the cellular origins and fate of SPP1-associated VSMC populations remain incompletely understood. We generated a novel Spp1-rSTOPr-Cre (Spp1Cre) knock-in mouse line in which Cre recombinase is expressed from the endogenous Spp1 locus following Dre-mediated excision of a rox-flanked transcriptional STOP cassette. Correct targeting of the knock-in allele was validated by internal, 5' junction, 3' junction, and long-range PCR analyses, as well as Sanger sequencing. To establish an intersectional lineage-tracing strategy, Spp1Cre mice were crossed with Myh11DreERT2 and Rosa26-RSR-LSL-tdTomato-LSL-eGFP reporter mice, enabling permanent labeling of VSMC-derived populations following activation of the endogenous Spp1 locus. Under physiological conditions, GFP-positive cells were detected at low frequency within the vascular wall and were predominantly negative for the contractile markers ACTA2 and MYH11. As a proof-of-principle application, GFP-positive cells markedly expanded within atherosclerotic lesions induced by PCSK9-AAV and high-fat diet feeding. These lineage-traced cells remained largely ACTA2- and MYH11-negative, consistent with a modulated phenotype. Notably, only a minority of GFP-positive cells expressed SPP1 or fibronectin at the time of analysis, demonstrating the utility of permanent lineage tracing for tracking cells with a history of endogenous Spp1 activation during vascular remodeling. We report the generation and validation of a novel Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of VSMC-derived populations that have activated the endogenous Spp1 locus. This genetic resource provides a valuable platform for investigating the origin, fate, and phenotypic evolution of Spp1-associated VSMC populations during vascular remodeling and cardiovascular disease.
Severe beta-blocker (BB) poisoning, with or without calcium channel blocker (CCB) co-ingestion, can cause refractory cardiovascular collapse and mortality. Intravenous lipid emulsion (ILE) has been used as a rescue therapy in selected severe cases, although its definitive clinical role remains uncertain. This systematic review summarizes published human case reports and case series describing ILE administration in BB with or without CCB toxicity. Databases including Medline, PubMed, EMBASE, and Google Scholar were searched from inception to December 31, 2024. Patient characteristics, poisoning details, pre-ILE clinical status, co-interventions, ILE dosing, hemodynamic and neurologic responses, and outcomes were extracted and analyzed using non-parametric methods. Twenty-two studies including 28 cases were identified, comprising 15 cases of isolated BB toxicity and 13 cases of combined BB and CCB toxicity. ILE was administered mainly as a rescue intervention for cardiovascular collapse or cardiac arrest; 17 patients (60.7%) were intubated and 10 (35.7%) required cardiopulmonary resuscitation before ILE administration. Hemodynamic improvement after ILE was reported in 21 cases (75.0%), and five patients died, corresponding to an overall mortality rate of 17.9%. Favorable discharge status was significantly associated with the absence of pre-ILE cardiopulmonary resuscitation, post-ILE clinical improvement, and blood pressure improvement after ILE. No significant association was observed between cumulative ILE dosage and clinical outcomes. Although these findings are limited by case-level evidence, publication bias, and confounding co-interventions, they support continued consideration of ILE as a last-resort rescue therapy in selected life-threatening BB/CCB poisonings rather than routine early intervention.
Background/Objectives: Metainflammation is a chronic low-grade inflammatory state driven by excessive nutrition and obesity. It is associated with adipocyte dysfunction, altered adipokine secretion, and the development of insulin resistance, which contributes to dysglycemia and hyperglycemia. Recent initiatives emphasize earlier recognition of pathological processes to enable timely detection and primary prevention of adverse cardiovascular outcomes. Metainflammation has traditionally been assessed using serum C-reactive protein (CRP) levels and several proposed indices, with inconsistent performance due to chronic inflammation-related changes in blood cell counts. This study aimed to evaluate a newly proposed MetaLGI score as a laboratory-based tool for identifying pronounced metainflammation in patients with metabolic syndrome. Methods: Patients with metabolic syndrome were assessed for metainflammation using the newly proposed MetaLGI score and compared with previously suggested indices and CRP-based definitions. The ability of these approaches to identify pronounced metainflammation and associated hematological and metabolic alterations was evaluated. Results: The MetaLGI score demonstrated superiority in recognizing pronounced metainflammation in patients with metabolic syndrome compared to previous indices. Additionally, the proposed laboratory definition of metainflammation showed better performance in identifying patients with increased platelet counts, highlighting its relevance for inflammation-related cardiovascular thrombosis. MetaLGI also outperformed earlier proposals in identifying patients with increased β-cell burden. Conclusions: The newly proposed MetaLGI score represents a superior and widely available laboratory-based method for detecting pronounced metainflammation in patients with metabolic syndrome. Its improved ability to identify increased platelet counts and β-cell burden suggests potential value for early risk stratification and primary prevention of cardiometabolic complications.
Ambient fine particulate matter (PM2.5) is a leading global environmental risk factor for cardiovascular disease. Although PM2.5 exposure is known to lead to mitochondrial dysfunction, the precise metabolic mechanisms underlying this effect remain incompletely understood. In this study, we investigated the role of the mitochondrial deacetylase Sirt3 in PM2.5-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiac organoids (hiPSC-COs), a physiologically relevant multicellular model. Our results demonstrated that PM2.5 exposure compromised the contractile function of COs. Specifically, it induced the expression of myocardial injury markers and triggered a series of mitochondrial impairments, including structural damage, inflammatory response, oxidative stress and loss of membrane potential. Mechanistically, exposure of COs to PM2.5 suppressed Sirt3 expression, leading to increased acetylation and decreased activity of malate dehydrogenase 2 (Mdh2), a key enzyme in the tricarboxylic acid (TCA) cycle. This disruption resulted in reduced levels of TCA cycle metabolites and a severe ATP deficit. Pharmacological activation of Sirt3 with dihydromyricetin attenuated the PM2.5-induced mitochondrial dysfunction, restored ATP levels and improved contractility. Our findings elucidate that PM2.5 impairs cardiac energy metabolism via the Sirt3/Mdh2 pathway, identifying Sirt3 as a potential therapeutic target for mitigating PM2.5-related cardiovascular dysfunction.