BACKGROUND:Giant coronary artery aneurysms are rare and may cause thrombosis, distal embolization, and myocardial infarction. Owing to their low prevalence, optimal management remains uncertain. CASE SUMMARY:A 56-year-old man presented with a non-ST-elevation myocardial infarction. Coronary angiography showed diffuse coronary ectasia and aneurysms, chronic right coronary artery occlusion, and no significant obstructive stenosis. Percutaneous revascularization failed because of the complex aneurysmal anatomy. Three years later, recurrent angina prompted multimodality imaging. Cardiac magnetic resonance revealed preserved left ventricular ejection fraction, inferior wall akinesia, transmural late gadolinium enhancement consistent with prior infarction, and new lateral wall motion abnormalities. Cine and tissue-characterization sequences suggested a giant partially thrombosed left circumflex aneurysm, confirmed by coronary computed tomography angiography, which demonstrated an hourglass-shaped aneurysm with minimal residual lumen. The patient underwent successful thrombectomy, capitonnage, and triple coronary artery bypass grafting. DISCUSSION:Multimodality imaging is essential for diagnosis and surgical planning, whereas treatment should be individualized according to aneurysm morphology and clinical presentation. TAKE-HOME MESSAGES:Thrombosed coronary artery aneurysms may be underestimated by coronary angiography because of limited opacification of the aneurysmal sac. Multimodality imaging, integrating coronary computed tomography angiography and cardiac magnetic resonance with angiography, provides complementary information on aneurysm anatomy, thrombus burden, vessel wall characteristics, and myocardial involvement, thereby supporting diagnosis and individualized management.

Aims:Compared with intravenous iron, oral iron is less expensive, avoids healthcare complexities, and reduces the risk of iron overload. However, conventional oral formulations have not improved clinical outcomes in heart failure (HF) and iron deficiency (ID), largely due to poor absorption. Sucrosomial iron (SI) partially bypasses hepcidin-controlled absorption and showed favorable effects in a small case-control study, warranting further evaluation in a randomized trial. Methods:The Effect of Oral sucRosomIal Iron on exerciSE Capacity and Quality of Life in Patients With Heart Failure (RISE-HF; NCT06270498) is a randomized, placebo-controlled, double-blind study enrolling 60 patients with HF with left ventricular ejection fraction <50%, ID (transferrin saturation (TSAT) < 20%), ferritin <400 μg/L and hemoglobin (Hb) 10-16 g/dL. Participants are randomized 1:1 to receive SI (Sideral Forte®: sucrosomial iron 30 mg + 70 mg vitamin C) or placebo for 24 weeks, with daily dose tailored to Hb (2 capsules for Hb 10-13.9 g/dL; 1 capsule for Hb 14-16 g/dL). Co-primary endpoints are changes from baseline to week 12 in exercise capacity, assessed by the 6-min walk test (6MWT) distance, and in quality of life, assessed by the Kansas City Cardiomyopathy Questionnaire-12. Secondary endpoints include changes in individual co-primary endpoints at week 24, effects on iron status and oxidative stress biomarkers, N-terminal pro type-B natriuretic peptide and echocardiographic indices of cardiac function, and gastrointestinal tolerability. Conclusions:RISE-HF will determine whether SI can safely improve exercise capacity, quality of life, and iron status in patients with HF and TSAT-defined ID, justifying a larger multicenter trial.

Abstract Background and aims Leptomeningeal collateral (LMC) circulation helps preserve brain tissue during acute ischemic stroke (AIS), with poor collateral status predicting worse outcomes. This study assessed the association between asymmetric dimethylarginine (ADMA), LMCs, infarct volume, and oxidative stress in 101 AIS patients with large vessel occlusion within 6h or wake-up stroke. Methods LMC status was graded using the Menon score (poor, intermediate, or good) on CT angiography, and recanalization was assessed by the modified Thrombolysis in Cerebral Infarction score. Serum ADMA, NADPH oxidase 2 (NOX2), and nitric oxide (NO) levels were measured at admission (<6h, T0), 24h (T1), and 48h (T2). Results Among patients, 43.1% had good, 35.3% intermediate, 21.6% poor LMC status. Higher admission ADMA levels were significantly associated with poor LMC at T0 (p=0.028) and more severe neurological deficits at T1 and T2 (p=0.005, p=0.008). ADMA levels increased over time (p=0.046), and correlated with NOX2 at T1 (p<0.001). Rising NOX2 was associated with increased neutrophils (p=0.013) and decreased lymphocytes (p=0.006). Conclusions ADMA may impair endothelial function by reducing NO availability and enhancing NOX2-driven oxidative stress. These findings support a role for the ADMA-NO-NOX2 axis in limiting collateral circulation. Targeting this axis may represent a therapeutic strategy to improve outcomes in AIS. Conflict of interest Manuela De Michele: nothing to disclose

PURPOSE:Heated tobacco products (HTPs) are devices that heat tobacco to high temperatures, rather than combusting it to generate smoke. The potential impact of HTPs on the body is not yet fully understood, as they are relatively recent products. The aim of this multidisciplinary study was to evaluate potential associations between the use of HTPs and both general and system-specific vital parameters in the enrolled subjects in order to determine whether these devices may be harmful and capable of inducing clinical, biochemical, or functional alterations compared to nonsmokers (non-SMs). MATERIALS AND METHODS:In this pilot study, the population consisted of 18 exclusive HTP users and 10 non-SMs. Spirometry was performed to assess respiratory function and blood sampling was used to evaluate the presence of oxidative stress (OS) biomarkers. Hemostatic variations and platelet aggregation were assessed using the total thrombus formation analysis system (T-TAS). Finally, ophthalmological examinations and optical coherence tomography angiography (OCTA) were performed to analyze the structural characteristics and chorioretinal vascular flow parameters. RESULTS:Hemorheological parameters revealed accelerated thrombus formation and prolonged thrombus stability on T-TAS, along with increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), or NADPH oxidase 2, levels. OCTA also revealed a statistically significant reduction in choriocapillaris flow (Ch-Flow) in HTP users. CONCLUSIONS:Alterations in primary hemostasis, OS, and chorioretinal microvascular perfusion highlight the need for further research in a larger cohort with higher mean age and longer cumulative exposure to HTPs to confirm these preliminary findings.

Background: Intense physical exercise induces oxidative stress and inflammation in adult professional athletes, but data on adolescent elite athletes remain limited. Methods: Twenty-four elite adolescent soccer players were recruited and evaluated three times: pre-season baseline (T0), after one month of pre-season training (T1), and at the end of the first half of the competitive season (T2, approximately 4 months after T0). Saliva samples were collected as non-invasive surrogate indicators reflecting oxidative stress- and endothelial-related signaling. In vitro studies were performed on endothelial cells exposed to H2O2 concentrations observed in athletes. Results: Athletes showed a significant increase in salivary oxidative stress markers (NOX2 levels and H2O2) at T1 and T2 versus T0. Endothelial impairment was evidenced by reduced salivary NOx concentration and elevated endothelin (ET-1) levels. In vitro, endothelial cells exposed to H2O2 (8 μM) showed increased sNOX2-dp and ET-1 levels, reduced eNOS phosphorylation, and impaired tube formation (mesh number and area) compared with untreated cells. NOX2ds-tat treatment reduced cell damage and restored angiogenic capacity. Conclusions: Our findings indicate that adolescent elite athletes experience significant salivary oxidative stress- and endothelial-related alterations, potentially reflecting cardiovascular stress. These results underscore the importance of cardiovascular monitoring and the potential benefits of antioxidant strategies, even in young athletes participating in high-intensity sports.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes independently contribute to increased gut permeability. Whether metabolic alterations of type 2 diabetes mellitus (T2DM) are further increased by the concomitant presence of MASLD and may explain cardiovascular risk is unknown. We analyzed differences in biomarkers of gut permeability alteration related low-grade endotoxemia and oxidative stress in T2DM with or without MASLD. Enrolled patients were included if they had a diagnosis of T2DM. In the presence of hepatic steatosis, the finding of any cardiometabolic risk factors would confer a diagnosis of MASLD if there are no other causes of hepatic steatosis. Blood samples were collected for oxidative stress and gut permeability evaluation. Overall, 190 patients were included, of which 95 had concomitant MASLD and 95 had no concomitant MASLD. Patients with MASLD had significantly higher values of lipopolysaccharide (LPS) and zonulin compared with patients without MASLD. Patients with MASLD have significantly higher values of NOX-2 activity and hydrogen peroxide compared with patients without MASLD. Linear correlation analysis demonstrated a significant and direct correlation between LPS and zonulin (R = 0.47, p = 1.3e-11). These results support the hypothesis that patients with MASLD exhibit an increase in gut permeability alteration related low-grade endotoxemia and oxidative stress compared with patients without MASLD. Antioxid. Redox Signal. 00, 000-000.

Takotsubo syndrome (TTS) is an acute and reversible heart failure condition characterized by transitional left ventricular systolic dysfunction without obstructive coronary artery disease. Although sympathetic hyperactivation is considered a key pathogenic mechanism, the contribution of gut-derived endotoxemia and oxidative stress is still unclear. Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, may translocate from the gut into the bloodstream and increase oxidative stress through activation of NADPH oxidase 2 (NOX2), nitric oxide (NO) depletion and endothelial dysfunction. This study aimed to evaluate circulating LPS levels in TTS and investigate their association with NOX2 activation, oxidative stress, and endothelial dysfunction. Twenty consecutive patients with TTS and 20 age- and sex-matched healthy controls were included. Within 48 h of admission, fasting blood samples were collected to assess soluble NOX2-derived peptide (sNOX2-dp), hydrogen peroxide (H2O2), NO metabolites (NOx), LPS, and zonulin. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Compared with controls, TTS patients had significantly higher serum levels of sNOX2-dp, H2O2, LPS, and zonulin, lower NOx and impaired FMD. sNOX2-dp was positively correlated with LPS (Rs = 0.539, p < 0.001) and zonulin (Rs = 0.331, p = 0.037) and inversely correlated with FMD (Rs = −0.462, p = 0.003). NOx correlated negatively with H2O2, zonulin and LPS. In multivariable analysis, LPS was the only independent predictor of FMD (β = 0.498, SE = 0.126, p = 0.001) and sNOX2-dp (β = −0.572, SE = 0.034 p < 0.001); FMD (β = −0.347, SE = 0.455, p = 0.005), H2O2 (β = 0.445, SE = 0.155, p < 0.001), and zonulin (β = 0.298, SE = 2.309, p = 0.016) emerged as independent predictors of LPS (adjusted R2 = 0.585). TTS is associated with low-grade endotoxemia, NOX2-driven oxidative stress, reduced NO bioavailability, and endothelial dysfunction. The independent association between LPS and NOX2 activation supports a potential gut–vascular axis in TTS pathophysiology.

Aging is associated with enhanced platelet activation that may contribute to the occurrence of cardiovascular events. However, the mechanism linking aging with platelet activation is not fully understood. The objective of this study is to investigate the relationship between aging, platelet Cox-1 expression, and thromboxane (Tx) B2 production in patients with atrial fibrillation. Serum Cox-1 and TxB2 were measured in 134 patients with atrial fibrillation. Correlations were assessed between age, Cox-1, and TxB2. A robust mediation analysis evaluated whether Cox-1 mediates the association between age and TxB2. In vitro experiments were performed in 20 patients to evaluate the effect of aspirin on platelet TxB2 production and to quantify platelet Cox-1 expression across age groups (i.e., < or ≥65 years). Serum Cox-1 and TxB2 progressively increased by decades of age. A positive and significant correlation was found between age and Cox-1 (R = 0.42, p-values < 0.01), age and TxB2 values (R = 0.44, p-value < 0.01), and Cox-1 and TxB2 (R = 0.5, p-value < 0.01). Cox-1 partially and significantly mediated the effect of age on TxB2 (β = 5.23, 95% confidence interval [2.33-8.63]) for the effect of age on TxB2. In vitro analysis showed a reduced inhibitory effect of aspirin on platelet TxB2 production in old compared to young subjects (IC50 97 μM and 49 μM in ≥ and <65 years, respectively) that was paralleled by Cox-1 overexpression in patients ≥65 years. Platelet Cox-1 expression was inversely related with aspirin inhibitory effects (R = -0.640, p-value < 0.01). Aging is associated with a concomitant increase in Cox-1 concentration and TxB2 production and an impaired ability of aspirin to inhibit Cox-1.

Background: Enhanced platelet activation contributes to the increased cardiovascular risk of elderly patients with atrial fibrillation. The biological mechanisms underlying this phenomenon are not fully clarified. This study investigated whether age-related increases in serum thromboxane B₂ (TxB₂) are associated with platelet cyclooxygenase-1 (Cox-1) upregulation in older individuals. Methods: Serum levels of Cox-1 and TxB₂ were assessed in patients with atrial fibrillation enrolled between 2022 and 2023. A subset of participants underwent in vitro analyses to evaluate the inhibitory effect of aspirin on platelet TxB₂ generation and to quantify platelet Cox-1 expression across different age groups (<65 vs. ≥65 years). The relationship between Cox-1 expression and aspirin-mediated inhibition of TxB₂ was also explored. Associations were analyzed using Spearman correlation, and mediation analysis was performed to assess indirect effects. Results: The study included 134 patients. Age showed a positive correlation with both Cox-1 expression (R = 0.42, p <0.01) and TxB₂ levels (R = 0.44, p <0.01). Additionally, Cox-1 expression was positively associated with TxB₂ concentrations (R = 0.50, p <0.01). Mediation analysis demonstrated that Cox-1 partially mediated the relationship between age and TxB₂ levels (β = 5.23, 95% CI: 2.33–8.63). In vitro experiments revealed a reduced sensitivity to aspirin in older patients, as reflected by higher IC₅₀ values for inhibition of platelet TxB₂ production (96.78 μM in ≥65 years vs. 48.92 μM in <65 years). This reduced response was accompanied by increased platelet Cox-1 expression in the elderly group. Moreover, higher Cox-1 levels were inversely correlated with aspirin-induced inhibition of platelet TxB₂ (R = −0.64, p <0.01). Conclusions: Advancing age is associated with increased thromboxane production, driven in part by platelet Cox-1 upregulation. This alteration is accompanied by a reduced capacity of aspirin to suppress Cox-1 activity, potentially contributing to the heightened thrombotic risk observed in elderly patients.

Oxidative stress is considered one of the cancer hallmarks, influencing tumor initiation, progression, and metastasis. High levels of reactive oxygen species (ROS) impair the effectiveness of the immune response in cancer patients. We examined changes in oxidative stress during immunotherapy, exploring the relationship between the immune system and clinical parameters related to oxidative burden. Several T-cell and myeloid subsets from 79 metastatic non-oncogene-addicted non-small-cell lung cancer (NSCLC) patients were analyzed using flow cytometry. Additionally, 20 cytokines were measured in serum samples, and sNox2-dp levels, an indicator of NOX2 activity, were assessed by ELISA. Seventy-nine healthy donors served as controls. The data showed that cancer patients had higher levels of sNox2-dp compared to healthy donors (p < 0.0001). Elevated sNox2-dp levels were associated with inflammation-related comorbidities (p = 0.008) and platelet counts (p = 0.03) in NSCLC patients. Furthermore, sNox2-dp displayed a negative correlation with immune cells involved in activation, such as proliferating (Ki67+) CD8+, PD1+ and effector lymphocytes, and a positive correlation with immunosuppressive PMN-MDSCs and inflammatory soluble immune factors, including IL1α, IL1β, IL6, IL10, CCL3, and CCL4. Oxidation levels decreased after immunotherapy (p = 0.04) and increased only in non-responder patients (p = 0.02). Oxidative stress may be indirectly affected by immunotherapy and could serve as a novel tool to identify responding patients in the NSCLC setting.

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in clinical practice, and its global health burden is progressively rising due to the aging of the world population, progressively higher prevalence of obesity, and improved attention to its early detection; AF is linked to increased risk of several complications, as well as death, stroke and peripheral embolism. In recent years many efforts have been made to fully understand the pathophysiology of AF and its complications. Several epidemiological studies have been conducted to early identification of AF, in order to pay more attention to AF risk factors, including arterial hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea syndrome (OSAS), physical inactivity, and alcohol excess.While the traditional view attributes the primary cause of AF onset to myocardial remodelling (i.e. atrial dilatation, ventricular hypertrophy), cutting-edge research has increasingly highlighted a pivotal role for systemic and myocardial inflammation in the etiology of this arrhythmia.In this study we aimed to evaluate the clinical presentation and the inflammatory immunophenotype of individuals presenting with AF episode, evaluating several biomarkers, such as IFN-γ and thromboxane B2 (TXB2), a potent vasoconstrictor and promoter of platelet aggregation.

Atrial fibrillation (AF) is associated with an increased risk of major adverse cardiovascular events (CVEs) including myocardial infarction, ischemic stroke and peripheral arterial ischemic events despite optimal anticoagulant therapy. Matrix metalloproteinase 2 (MMP-2) levels have been associated with endothelial dysfunction and atherosclerosis, and in AF patients, MMPs seem to play a role in atrial fibrosis but no solid data on the association with CV risk do exist. We measured MMP-2 plasma levels, and its selective naturally occurring inhibitor TIMP-2 in 211 AF patients with (n = 86) or without (n = 125) CVEs, in a nested case-control study from the prospective ATHERO-AF study. The two groups were balanced for clinical characteristics. The median value of MMP-2 was 731 ng/ml in patients with and 953 ng/ml in patients without CVEs (p < 0.05). ROC curve analysis identified a cut-off value of 825 ng/ml associated with CVEs. Patients with MMP-2 above this level had a lower incidence of CVEs (OR: 0.38, CI 0.2-0.6) and stroke (OR 0.37 CI 0.1-0.9). Additionally, multivariable Cox proportional hazards analysis confirmed an inverse association between high levels of MMP-2, CVEs and stroke (HR 0.563, 95%CI 0.358-0.886, p = 0.013 and HR 0.335, 95%CI 0.146-0.771, p = 0.010, respectively). Results were confirmed using continuous values. These data suggest a possible protective role of MMP-2 against CVEs occurrence in patients with AF and highlight the need of further investigations on the potential role of MMP-2 as a prognostic biomarker in non-valvular AF.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by liver disease progression and cardiovascular disease (CVD). The mechanism linking MASLD with CVD is not fully understood. Here, we report experimental and clinical studies suggesting that platelet activation may be implicated in the pathogenesis of MASLD and CVD.

Good leptomeningeal collaterals (LMCs) after large vessel occlusion (LVO) extend the time window for endovascular therapy. The mechanisms regulating LMC activation are not fully understood. The aim of this study was to investigate the potential role of two vasoactive molecules endothelin-1 (ET-1)—a vasoconstrictor agent—and nitric oxide (NO)—a vasodilator agent—in the regulation of post-stroke LMCs. Ischemic stroke patients within 6 h of LVO were included. Collateral status was assessed using the Menon scoring system based on computed tomography angiography scans. Patients were accordingly divided into three groups: poor, intermediate, and good LMCs. Recanalization was evaluated using the modified thrombolysis in cerebral infarction (mTICI) score. Serum levels of ET-1 and NO were measured at three time points: T0 (<6 h), T1 (24 h), and T2 (48 h). A total of 105 patients were enrolled (mean age 76 ± 12.8 years): 44 with good (46.2%), 36 with intermediate (37.8%), and 22 with poor LMCs (23.1%). NO values decreased, whereas ET-1 values increased from T0 to T1 in all groups of patients. No significant association was found between serum ET-1 levels and collateral status. Higher ET-1 levels at T1 correlated with poor outcome regardless of the LMC status or the degree of recanalization (p = 0.030). A significant linear positive correlation was revealed at T0 between high levels of ET-1 and the neutrophil count (Spearman’s rho = 0.236, p = 0.035). Subgroup analysis showed a significant inverse correlation at T1 between NO and the collateral score (Spearman’s rho = −0.251, p = 0.021). Although we observed no significant association between LMC score and serum ET-1 concentrations, at 24 h higher ET-1 serum levels were predictive of poor outcome and higher NO levels were correlated with poor collateral status. These findings may indicate an inadequate microvascular reperfusion, possibly due to ET-1-mediated vasoconstriction, neutrophil activation, and NO-mediated oxidative stress, suggesting their potential role in the no-reflow phenomenon.

Introduction/Background: PCSK9 has been shown to induce neutrophil extracellular trap (NET) formation in experimental models, contributing to thrombotic processes. Heterozygous familial hypercholesterolaemia (HeFH), characterized by elevated LDL-C and increased cardiovascular risk, provides a relevant human model to explore this mechanism. However, the role of PCSK9 in NET formation in humans remains unclear. Research Questions/Hypothesis: This study aimed to determine whether PCSK9 promotes NET formation and thrombotic activation in HeFH patients, and whether PCSK9 inhibitors (PCSK9-I) can reduce these effects. The involvement of cathepsin G and other pathways in NETosis and thrombosis was also investigated. Goals/Aims: The aims were to assess the impact of PCSK9 on NET-associated thrombosis in HeFH. NETosis, platelet activation, and coagulation markers and elucidate the molecular mechanisms by which PCSK9 induces NET formation and thrombus growth. Methods/Approach: 40 HeFH patients on maximal statin ± ezetimibe therapy were studied before (BP) and after (AP) six months of PCSK9-I. 20 healthy subjects (HS) served as controls. Circulating markers of NETosis, platelet and coagulation activation were measured. In vitro, neutrophil-platelet mixtures from healthy donors were incubated with plasma from BP, AP, and HS to assess NET formation, platelet/coagulation activation, and thrombus growth. The effects of recombinant PCSK9 (hrPCSK9) on these processes were also evaluated, with or without inhibitors of PCSK9, CD36, cathepsin G, and PAD4. Results/Data: HeFH patients showed significantly higher NETs, platelet activation, and thrombotic markers than HS, all of which were reduced following PCSK9-I treatment. In vitro, plasma from BP induced greater NETosis, platelet activation, and thrombus formation compared to plasma from AP or HS. Incubation of hrPCSK9 with neutrophil-platelet mixtures enhanced NET formation, cathepsin G release, and thrombus growth. These effects were suppressed by inhibitors of PCSK9, CD36, cathepsin G, and PAD4, supporting a cathepsin G-dependent mechanism of PCSK9-mediated thrombotic process. Conclusions: PCSK9 contributes to NET formation and thrombotic activation in HeFH patients via a mechanism involving cathepsin G. PCSK9-I therapy reduces these effects, revealing a novel antithrombotic benefit beyond lipid lowering. These findings provide new insight into PCSK9’s role in cardiovascular disease and support its inhibition in FH management.

Despite significant advances, the prevention and management of cardiovascular disease remain challenging, especially for ischemic heart disease (IHD). Current clinical decision-making relies heavily on physician expertise, guideline-directed therapies, and static risk scores, which often inadequately accommodate individual patient complexity. Machine learning (ML) and artificial intelligence (AI), particularly reinforcement learning (RL), may augment current physician-driven approaches and provide enhanced cardiovascular disease prevention and management. Indeed, offline RL refers to a class of ML algorithms that learn optimal decision-making policies from a fixed dataset of previously collected experiences—such as electronic health records or registries—without the need for active, real-time interaction with the clinical environment. This approach enables the safe development of treatment strategies in high-stakes domains where experimentation on live patients could be unethical or impractical. Notably, offline RL models hold the promise of optimizing decision-making in complex clinical settings, such as revascularization strategies for coronary artery disease. However, challenges remain in integrating AI into practice, ensuring interpretability, maintaining performance, and proving cost-effectiveness. Ultimately, validation, integration, and collaboration among clinicians, researchers, and policymakers are crucial for transforming AI-driven solutions into practical, patient-centered cardiovascular care improvements, pending prospective (and hopefully randomized) validation.