Search Results (143)

Arteriogenesis, the growth of pre-existing arterioles into functional collateral arteries, represents a key adaptive response to severe arterial stenosis. This process is driven by hemodynamic forces and a tightly coordinated inflammatory cascade. Here, we investigated the effects of pharmacological stimulation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway using the phosphodiesterase-5 (PDE5) inhibitor Sildenafil on collateral vessel growth in a murine model of femoral artery ligation (FAL). Flow cytometric analyses revealed that Sildenafil treatment significantly enhanced platelet–leukocyte aggregate formation, a prerequisite for the subsequent initiation of a localized perivascular inflammation. Histological and immunofluorescence analyses further demonstrated a marked increase in mast cell recruitment and degranulation at early time points (days 1 and 3 post-FAL). In addition, Sildenafil promoted perivascular macrophage accumulation on days 3 and 7, with a pronounced shift toward an M2-like pro-regenerative polarization state, ultimately resulting in the enhanced proliferation of vascular cells and the enlargement of collateral diameters. Together, these findings identify Sildenafil as a potent enhancer of arteriogenesis through coordinated immune cell activation, stimulating vascular cell proliferation along with positive collateral outward remodeling. Thus, Sildenafil emerges as a promising therapeutic candidate to promote collateral artery growth in cardiovascular occlusive diseases. Full article

Vascular dysfunction lies at the core of cardiovascular diseases—the leading cause of global morbidity and mortality. Despite their prevalence, therapeutic options remain limited, in part due to an incomplete understanding of the molecular mechanisms driving vascular pathology. The integrated stress response (ISR), an evolutionarily conserved signaling network activated by diverse stressors, represents a critical but underexplored mechanism in vascular biology. This review examines the dual roles of the core ISR kinases—PERK, GCN2, HRI and PKR—in vascular homeostasis and pathology, including atherosclerosis, pulmonary hypertension, and angiogenesis. We develop a conceptual framework in which the ISR functions as a context-dependent, double-edged sword: while PERK and PKR promote inflammation, apoptosis, and vascular re-modeling, GCN2 mediates protective effects. The outcome of ISR activation is shaped by cell type, stress duration and intensity, and downstream signaling bias (e.g., ATF4 vs. CHOP dominance). We further discuss pharmacological ISR modulators—including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157—which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention. Full article

Background: Cardiovascular diseases, driven by platelet hyperactivation and thrombosis, remain the leading global cause of death. Excessive platelet activation contributes to atherosclerosis and thrombo-inflammatory disorders, underscoring the urgent need for safer and more effective antiplatelet agents. Objectives:Xanthium strumarium L. (X. strumarium) has been reported to exhibit a wide range of pharmacological effects, including anti-inflammatory and antioxidant activities. However, its antiplatelet and antithrombotic effects remain unexplored. Therefore, the present study aimed to comprehensively evaluate the antiplatelet and antithrombotic effects of X. strumarium through integrated in vitro and in vivo experiments. Methods: The principal bioactive compounds present in the X. strumarium extract were identified through GC–MS analysis. In vitro antiplatelet effects were evaluated via light transmission aggregometry, scanning electron microscopy (SEM), ATP and calcium mobilization assays, αIIbβ3 binding assay, clot retraction assay, and Western blotting. In vivo ferric chloride-induced (FeCl₃) murine thrombus model was established to evaluate thrombogenesis. Results: Our results demonstrated that X. strumarium at 25, 50, or 100 μg/mL significantly inhibited collagen, ADP, U46619, and thrombin-induced platelet aggregation. SEM revealed that X. strumarium pretreatment markedly preserved the resting platelet morphology and inhibited collagen-induced activation and shape changes. Further, the granule secretion, integrin-αIIbβ3 signaling, and the MAPK and PI3K/Akt pathways were also concentration-dependently inhibited. The in vivo blood flow rate and mice survival were improved, and H&E staining further revealed a concentration-dependent prevention of arterial occlusion following X. strumarium treatment. Conclusions: Collectively, X. strumarium demonstrated potent antiplatelet and antithrombotic effects, improving blood flow and survival while preventing arterial occlusion. Full article

Background/Objectives: Clopidogrel is a P2Y₁₂ receptor inhibitor commonly used as antiplatelet therapy for patients with cardiovascular occlusive diseases. However, its role in vascular remodeling remains poorly understood. Platelets orchestrate the sterile inflammation in arteriogenesis, an endogenous process to bypass an occluded artery. Therefore, we investigated the impact of P2Y₁₂-inhibition by Clopidogrel on arteriogenesis. Methods: In this study, we utilized a well-established murine hindlimb model of arteriogenesis. To quantify the growth of collateral arteries, we employed laser-Doppler perfusion measurements and immunohistological analysis of growing compared to resting collateral arteries. Additional immunofluorescence and histological stains were conducted to assess immune cell recruitment and activation. Whole-blood flow cytometry was performed to analyze platelet–leukocyte interactions, and complete blood counts were obtained to quantify leukocyte and platelet numbers. Results: The findings of this study demonstrate that Clopidogrel promotes perfusion recovery following the induction of arteriogenesis compared to controls, attributed to elevated levels of proliferating vascular cells. Furthermore, compared to controls, Clopidogrel treatment significantly enhanced platelet-leukocyte interactions, increasing perivascular mast cell recruitment and degranulation, finally resulting in regenerative macrophage accumulation required for collateral artery growth. Conclusions: Clopidogrel treatment boosts arteriogenesis by enhancing the local regenerative inflammation relevant for vascular cell proliferation. Therefore, P2Y₁₂ inhibition may represent a therapeutic option to effectively promote natural bypass growth in patients with cardiovascular occlusive diseases. Full article

Introduction: The neutrophil–lymphocyte ratio (NLR) has proven to be an inexpensive and easily available inflammatory marker for cardiovascular disease. The aim of the present study is to evaluate a possible association between preoperative NLR value and endovascular aneurysm repair (EVAR) outcomes. Methods: A multicentric retrospective study of patients undergoing EVAR in elective setting between 2015 and 2023 was performed. Preoperative NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count, and a cut-off of 5 was used as threshold for the analysis. Primary outcomes (technical success, endograft occlusion, AAA-related reintervention, endoleaks, and mortality rates) were compared between the NLR < 5 and the NLR > 5 group. Kaplan–Meier survival analysis was employed to assess overall survival and the incidence of long-term complications. Results: The study initially considered 1360 patients. Eventually, 823 patients were included in the study, of whom 129 (15.7%) with NLR > 5. The latter group presented a higher AAA diameter (59.1 mm vs. 55, mm; p = 0.004). Technical success was obtained in 98,9% of all enrolled patients. NLR values were significantly associated with ASA class (p = 0.014), involvement of the iliac arteries (p = 0.023), duration of ICU stays (p < 0.001), and overall length of hospitalization (<0.001). At Kaplan–Meier analysis, patient with NLR > 5 showed a significant lower survival rates (p = 0.006), while no significant differences were found in terms of endograft occlusion (p = 0.45), AAA-related reintervention (p = 0.63), and endoleaks (p = 0.49). Conclusions: This study highlights the association between the NLR value and an elevated risk of long-term mortality, highlighting its role as an indicator of the patient’s overall clinical condition rather than immediate surgical outcomes. Focusing on this selected group of patients can improve postoperative care and reduce long-term complications. Full article

Background: Thyrotoxicosis is a systemic condition with well-documented cardiovascular effects, but its role as a precipitant of acute coronary syndromes (ACS) is often overlooked. This review summarizes clinical cases and original studies from the last 20 years, describing ACS triggered by thyrotoxicosis. Methods: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, and Embase for reports published between 2004–2025. Only case reports and original articles were included. Data extracted included demographics, ECG findings, angiography results, thyroid function, etiology of hyperthyroidism, and outcomes. Results: A total of 35 cases were identified. The mean age was in the fourth decade of life, with a female predominance (57%, 20 out of 35). More than half of the patients presented with ST-segment elevation myocardial infarction (STEMI) or STEMI equivalents (21 out of 35; 60%). Electrocardiographic abnormalities most often involved anterior or inferior leads. Coronary angiography revealed normal vessels or diffuse vasospasm in 18 cases (51%), while thrombotic occlusion was observed in 4 cases (11%), spontaneous dissection in 2 cases (6%), and myocardial bridging in 3 cases (9%). The leading cause of thyrotoxicosis was Graves’ disease (≈65%), followed by painless thyroiditis, iatrogenic causes, and gestational hyperthyroidism. Thyroid storm was reported in approximately 20% of cases and was associated with malignant ventricular arrhythmias or sudden cardiac death. Conclusions: Thyrotoxicosis should be recognized as a rare but important trigger of ACS, especially in young patients without traditional risk factors. Pathophysiological mechanisms include coronary vasospasm, increased myocardial oxygen demand, and hypercoagulability. Early recognition may prevent unnecessary revascularization and optimize outcomes through integrated endocrine and cardiac management. Full article

Background: Rituximab is a monoclonal antibody targeting CD20, commonly used to treat autoimmune diseases such as granulomatosis with polyangiitis (GPA) and rheumatoid arthritis. While generally well-tolerated, serious adverse events, including infusion reactions and infections, are well-documented. Case Summary: We report a rare case of rituximab-induced ST-elevation myocardial infarction (STEMI) in a 26-year-old woman with no cardiovascular risk factors. She developed crushing chest pain after her first 1 g rituximab infusion, with recurrent symptoms upon re-exposure. Cardiac catheterization revealed a left circumflex artery occlusion. Additional workup showed c-ANCA positivity, cryoglobulinemia, pauci-immune glomerulonephritis, and findings consistent with GPA. Rituximab was discontinued, and she was transitioned to steroids, cyclophosphamide, and leuprolide, with no further cardiac events. Discussion: This is the first reported case in a young, previously healthy woman. Clinicians should consider rituximab-associated myocardial injury, especially in autoimmune or hypercoagulable states. Take-Home Message: Remain vigilant for cardiac events during rituximab infusions in patients with inflammatory diseases. Full article

Background/Objectives: Thrombosis, a critical condition that can have severe consequences, such as myocardial infarction and cerebral infarction, can be induced by steroid drugs. Although the mechanisms for inducing thrombosis are known for some types of steroid drugs, much remains unknown about the differences in the tendency and mechanisms for thrombosis. Methods: To address this knowledge gap, we analyzed the relationship between thrombosis and steroid use by utilizing the U.S. Food and Drug Administration Adverse Event Reporting System database. From the database, we extracted demographic and drug information and information on reported adverse events from 2004 to 2024. We characterized drugs according to physiological function, receptor specificity, and Anatomic Therapeutic Chemical classification and calculated the proportion of steroid drugs that were likely to induce thrombosis. Results: Among steroid drugs, sex hormones such as androgens, progestogens, and estrogens appeared to have particularly high potential for causing thrombotic events. Results of principal component analysis and cluster analysis indicated that sex hormone preparations were associated with an increased risk of venous thrombosis. In addition, cardiovascular medications and mineralocorticoids, which are used to treat diseases of major organs, showed a tendency to induce large-vessel occlusions. Conclusions: These findings may be useful for selecting steroid drugs for patients who are at risk for similar adverse effects. Full article

Background and Aims: Placental growth factor (PlGF) is an important predictive marker of pregnancy complications such as preeclampsia. The aim of this study is to assess whether PlGF measured outside of pregnancy is a predictive marker for cardiovascular disease (CVD) risk in young women. Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study. PlGF concentrations, as well as systolic and diastolic blood pressure (SBP and DBP), cardiac outcomes, carotid-femoral pulse wave velocity, and central retinal arteriolar and venular calibres of 5077 women, were assessed six years after pregnancy, which was considered baseline. Four years after baseline, we measured blood pressure and intimal media thickness (IMT). Eight years after baseline, we measured blood pressure and the post-occlusive reactive hyperaemia index (PORH index). In addition, we examined the influence of pregnancy complications on these associations. Results: We found a positive association between PlGF levels with SBP (0.46, 95% CI 0.04; 0.89). PlGF was not associated with retinal or echocardiographic measurements. PlGF was positively associated with DBP after four years and with both SBP and DBP eight years after baseline, independent of the occurrence of pregnancy complications. PlGF was not associated with IMT or the PORH index. Conclusions: PlGF is associated with higher blood pressure. PlGF may, therefore, be used as a marker of hypertension. These results need to be replicated in an independent cohort study. Full article

A 62-year-old man presented with ST-elevation myocardial infarction and advanced tophaceous gout, despite long-term urate-lowering therapy. His history included chronic kidney disease, hypertension, heart failure, and atrial fibrillation. Examination revealed severe joint deformities with multiple tophi. Coronary angiography showed multivessel disease with critical right coronary artery stenosis, treated with primary percutaneous coronary intervention. Following a Heart Team consultation, the patient was bridged with cangrelor and underwent urgent hybrid coronary artery bypass grafting and left atrial appendage occlusion. This case highlights the systemic burden of treatment-refractory gout, with progressive cardiovascular and renal complications. Tophaceous gout represents a distinct, high-risk phenotype associated with increased mortality and reduced quality of life. Despite standard therapies, this patient experienced continued disease progression, prompting referral for advanced treatment with pegloticase and canakinumab. Multidisciplinary care and personalized strategies are essential in managing severe, refractory gout with multi-organ involvement. Full article

Background: Reduced-dose prasugrel is widely used in East Asia for acute coronary syndrome (ACS), but real-world data in diverse Asian populations are limited. This study evaluated its effectiveness and safety in Taiwanese patients. Methods: The PROMISE-TW Registry was a multicenter, retrospective study including 1167 patients with ACS or chronic coronary syndrome (CCS) treated with reduced-dose prasugrel (20 mg loading, 3.75 mg maintenance) across 13 hospitals in Taiwan from 2018 to 2022. The primary endpoint was 1-year major adverse cardiovascular events (MACEs: cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). Secondary outcomes included composite ischemic events and major bleeding (BARC 3–5). Results: Among enrolled patients (mean age 63.9 years; 81.2% male; 83% ACS), percutaneous coronary intervention was performed in 90.8%. At one year, MACEs occurred in 1.9%, composite ischemic events in 8.2%, and major bleeding in 0.8%. Subgroup analysis identified prior stroke, diabetes, and chronic total occlusion intervention as predictors of bleeding. Male sex, chronic kidney disease, and left circumflex artery intervention predicted higher ischemic risk. Conclusions:Reduced-dose prasugrel provided effective ischemic protection and low bleeding rates in Taiwanese patients, especially those with ACS. These findings support the clinical utility of dose-adjusted prasugrel in East Asian populations and highlight the importance of individualized risk assessment. Full article

Cigarette smoking is acknowledged as the most preventable risk factor for thrombogenesis-associated cardiovascular disease. Mice prenatally exposed to the thirdhand smoke (THS) form of tobacco exhibited a higher tendency to develop occlusive thrombosis, along with enhancement of several platelet functional responses. Our objective was to investigate whether prenatal (in utero) THS exposure impacts the platelet transcriptome, resulting in enhanced platelet functional responses, thereby underlying THS-associated thrombogenicity. Blood samples obtained from twenty male mice prenatally exposed to THS, along with an equal number of age-matched male mice exposed to clean air (CA) as a control, were divided into pools of five animals and used to prepare leukocyte and red blood cell-depleted platelets. RNA sequencing for mRNA and microRNA (miRNA) was utilized to analyze and compare the platelet expression profiles of the two exposure groups. RNA seq analyses revealed distinct changes in both gene expression and miRNA profiles, with 448 coding genes and 18 miRNAs significantly altered between the two groups. miRNA–mRNA interaction analysis highlighted 14 differentially expressed miRNAs that potentially target 120 of the differentially expressed genes in our data set. Interestingly, altered genes in miRNA–mRNA pairs were functionally enriched into pathways associated with platelet physiology, including platelet activation, signaling and aggregation, and cellular response to chemical stimuli. Our findings establish—for the first time—that prenatal exposure to THS modifies the platelet transcriptome, thereby rendering platelets hypersensitive to stimuli and more prone to thrombogenicity. Additionally, we illuminate the coordinated function of platelet miRNA and mRNA targets in mediating this response. Full article

Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19. Full article

The abnormal growth of smooth muscle cells (SMCs) contributes to the vascular remodeling associated with coronary artery disease, a leading cause of death in women. Estradiol (E2) mediates cardiovascular protective actions, in part, by inhibiting the abnormal growth (proliferation and migration) of SMCs through various mechanism. Since microRNAs (miRNAs) play a major role in regulating cell growth and vascular remodeling, we hypothesize that miRNAs may mediate the protective actions of E2. Following preliminary leads from E2-regulated miRNAs, we found that platelet-derived growth factor (PDGF)-BB-induced miR-193a in SMCs is downregulated by E2 via estrogen receptor (ER)α, but not the ERβ or G-protein-coupled estrogen receptor (GPER). Importantly, miR-193a is actively involved in regulating SMC functions. The ectopic expression of miR-193a induced vascular SMC proliferation and migration, while its suppression with antimir abrogated PDGF-BB-induced growth, effects that were similar to E2. Importantly, the restoration of miR-193a abrogated the anti-mitogenic actions of E2 on PDGF-BB-induced growth, suggesting a key role of miR-193a in mediating the growth inhibitory actions of E2 in vascular SMCs. E2-abrogated PDGF-BB, but not miR-193a, induced SMC growth, suggesting that E2 blocks the PDGF-BB-induced miR-193a formation to mediate its anti-mitogenic actions. Interestingly, the PDGF-BB-induced miR-193a formation in SMCs was also abrogated by 2-methoxyestradiol (2ME), an endogenous E2 metabolite that inhibits SMC growth via an ER-independent mechanism. Furthermore, we found that miR-193a induces SMC growth by activating the phosphatidylinositol 3-kinases (PI3K)/Akt signaling pathway and promoting the G1 to S phase progression of the cell cycle, by inducing Cyclin D1, Cyclin Dependent Kinase 4 (CDK4), Cyclin E, and proliferating-cell-nuclear-antigen (PCNA) expression and Retinoblastoma-protein (RB) phosphorylation. Importantly, in mice, treatment with miR-193a antimir, but not its control, prevented cuff-induced vascular remodeling and significantly reducing the vessel-wall-to-lumen ratio in animal models. Taken together, our findings provide the first evidence that miR-193a promotes SMC proliferation and migration and may play a key role in PDGF-BB-induced vascular remodeling/occlusion. Importantly, E2 prevents PDGF-BB-induced SMC growth by downregulating miR-193a formation in SMCs. Since, miR-193a antimir prevents SMC growth as well as cuff-induced vascular remodeling, it may represent a promising therapeutic molecule against cardiovascular disease. Full article

Background: Patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD) who undergo complete revascularization (CR) have a more favorable prognosis than those who receive incomplete revascularization (IR), as evidenced by recent randomized controlled trials. Despite the absence of a survival benefit associated with CR in these trials, positive outcomes were ascribed to combined endpoints, such as repeat revascularization, myocardial infarction, or ischemia-driven rehospitalization. In light of the significant burden that rehospitalization from STEMI imposes on healthcare systems, we examined the long-term effects of CR on ischemia-driven rehospitalization and cardiovascular (CV) mortality in STEMI patients with MVD. Methods: In our retrospective study, we included patients with STEMI and MVD who underwent successful primary percutaneous coronary intervention (PCI) at the University Medical Centre Ljubljana between 1 January 2009, and 11 April 2011. The combined endpoint was ischemia-driven rehospitalization and CV mortality, with a minimum follow-up period of six years. Results: We included 235 participants who underwent CR (N = 70) or IR (N = 165) at index hospitalization, with a median follow-up time of 7 years (interquartile range 6.0–8.2). The primary endpoint was significantly higher in the IR group than in the CR group (47.3% vs. 32.9%, log-rank p = 0.025), driven by CV mortality (23.6% vs. 12.9%, log-rank p = 0.047), as there was no difference in ischemia-driven rehospitalization rate (log-rank p = 0.206). Ischemia-driven rehospitalization did not influence CV mortality in the CR group (p = 0.49), while it significantly impacted CV mortality in the IR group (p = 0.03). After adjusting for confounders, there were no differences in CV mortality between CR and IR groups (p = 0.622). Predictors of the combined endpoint included age (p = 0.014), diabetes (p = 0.006), chronic kidney disease (CKD) (p = 0.001), cardiogenic shock at presentation (p = 0.003), chronic total occlusion (CTO) (p = 0.046), and ischemia-driven rehospitalization (p = 0.0001). Significant risk factors for the combined endpoint were cardiogenic shock at presentation (p < 0.001), stage 4 kidney failure (p = 0.001), age over 70 years (p = 0.004), female gender (p = 0.008), and residual SYNTAX I score > 5.5 (p = 0.017). Conclusions: Patients with STEMI and MVD who underwent CR had a lower combined endpoint of ischemia-driven rehospitalizations and CV mortality than IR patients, but after adjustments for confounders, the true determinants of the combined endpoint and risk factors for the combined endpoint were independent of the revascularization method. Full article