This comprehensive review aims to provide a thorough overview of the vital role that extracellular vesicles (EVs) play in endothelial dysfunction, particularly emphasizing how physiological factors—such as sex and aging—along with significant cardiovascular risk factors, influence this process. The review covers studies ranging from the first description of EVs in 1945 to contemporary insights into their biological roles in intercellular signaling and endothelial dysfunction. A comprehensive analysis of peer-reviewed articles and reviews indexed in the PubMed database was conducted to compile the information. Initially, Medical Subject Headings (MeSH) terms included keywords aimed at providing general knowledge about the role of EVs in the regulation of endothelial signaling, such as “extracellular vesicles”, “endothelium”, and “intercellular signaling”. Subsequently, terms related to the pathophysiological implications of EV interactions with endothelial dysfunction and cardiovascular disease were added, including “cardiovascular disease”, “sex”, “aging”, “atherosclerosis”, “obesity”, and “diabetes”. Additionally, the potential applications of EVs in cardiovascular disease were explored using the MeSH terms “extracellular vesicles”, “cardiovascular disease”, “biomarker”, and “therapeutic strategy”. The results of this bibliographical review reveal that EVs have the capacity to induce various cellular responses within the cardiovascular system and play a significant role in the complex landscape of endothelial dysfunction and cardiovascular disease. The composition of the EV cargo is subject to modification by pathophysiological conditions such as sex, aging, and cardiovascular risk factors, which result in a complex regulatory influence on endothelial function and neighboring cells when released from a dysfunctional endothelium. Moreover, the data suggest that this field still requires further exploration, as EV biology is continuously evolving, presenting a dynamic and engaging area for research. A deeper understanding of the molecular cargo involved in EV–endothelium interactions could yield valuable biomarkers for monitoring cardiovascular disease progression and facilitate the development of innovative bioengineered therapeutic strategies to enhance patient outcomes.

Endothelial cell dysfunction is the principal cause of several cardiovascular diseases that are increasing in prevalence, healthcare costs, and mortality. Developing a standardized, representative in vitro model of endothelial cell dysfunction is fundamental to a greater understanding of the pathophysiology, and to aiding the development of novel pharmacological therapies. We subjected human umbilical vein endothelial cells (HUVECs) to different periods of nutrient deprivation or increasing doses of H₂O₂ to represent starvation or elevated oxidative stress, respectively, to investigate changes in cellular function. Both in vitro cellular models of endothelial cell dysfunction-associated senescence developed in this study, starvation and oxidative stress, were validated by markers of cellular senescence (increase in β-galactosidase activity, and changes in senescence gene markers SIRT1 and P21) and endothelial dysfunction as denoted by reductions in angiogenic and migratory capabilities. HUVECs showed a significant H₂O₂ concentration-dependent reduction in cell viability (p < 0.0001), and a significant increase in oxidative stress (p < 0.0001). Furthermore, HUVECs subjected to 96 h of starvation, or exposed to concentrations of H₂O₂ of 400 to 1000 μM resulted in impaired angiogenic and migratory potentials. These models will enable improved physiological studies of endothelial cell dysfunction, and the rapid testing of cellular efficacy and toxicity of future novel therapeutic compounds.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are central regulators of monocyte and macrophage biology, shaping their survival, differentiation, migration, and effector functions. In monocytes and macrophages, ROS and RNS arise from endogenous sources, such as mitochondria, NADPH oxidases, and myeloperoxidase, and from exogenous stimuli including pathogens, damaged tissues, and environmental oxidants. These reactive intermediates converge on redox-sensitive pathways such as NF-κB, Nrf2/HO-1, mitochondrial ROS signalling, and the NLRP3 inflammasome, thereby integrating metabolic stress with inflammatory activation. Redox balance is a key determinant of macrophage polarization: heightened ROS and RNS production drives pro-inflammatory M1 programs, whereas tightly regulated oxidative signalling supports M2 phenotypes associated with tissue repair and resolution. In chronic inflammatory disorders, notably atherosclerosis, oxidative stress amplifies monocyte recruitment, foam-cell formation, plaque instability, and maladaptive immunometabolic responses. The aim of this review is to recapitulate the major sources and functions of ROS and RNS in monocytes and macrophages and to synthesize current evidence on how these pathways collectively maintain or disrupt immune homeostasis. We further highlight emerging therapeutic strategies, such as NOX inhibitors, mitochondrial-targeted antioxidants, and Nrf2 activators, that seek to restore redox balance and offer promising avenues for the treatment of cardiovascular and immune-mediated diseases.

Background: Myocardial fibrosis leads to ventricular dysfunction and worsened prognosis, especially after ST-segment elevation myocardial infarction (STEMI). Sodium–glucose cotransporter 2 inhibitors (SGLT2is) offer cardiovascular benefits by reducing markers of myocardial fibrosis and fibroblast activity. However, the effects of SGLT2i on myocardial fibrosis deposition among STEMI patients undergoing primary percutaneous coronary intervention (PCI) have not yet been evaluated. Study and Design: The effect of DAPAgliflozin on myocardial fibrosis and ventricular function in patients with STEMI (DAPA-STEMI) trial is a phase III, multicenter, randomized, double-blind, placebo-controlled trial. The study aims to assess the effects of dapagliflozin on myocardial fibrosis and ventricular function, evaluated using cardiac magnetic resonance (CMR), in STEMI patients undergoing primary PCI. Eligible patients were 30 to 85 years old and exhibited a left ventricular ejection fraction ≤ 50%. A total of 120 patients with STEMI were expected to be randomized 1:1 to receive dapagliflozin 10 mg or placebo daily for six months. The primary endpoint is the change in the extracellular volume fraction of the remote myocardium from baseline to six months, as measured by CMR. The secondary endpoints include changes in the circulating C-terminal propeptide of type I procollagen, N-terminal propeptide of type III procollagen, and Galectin-3 from baseline to six months. The study was stopped prematurely due to slow recruitment, with 54 enrolled patients, limiting the statistical power to detect changes in the primary endpoint between groups. Conclusions: The DAPA-STEMI trial will provide insights into the impact of dapagliflozin on myocardial fibrosis and ventricular remodeling in patients with STEMI undergoing primary PCI. Clinical Trial Registration Unique Identifier: NCT06619600

Background: Myocardial fibrosis plays a key role in adverse remodeling after ST-segment-elevated myocardial infarction (STEMI). The effect of sodium–glucose cotransporter 2 inhibitors (SGLT2is) on myocardial fibrosis deposition among patients with STEMI undergoing primary percutaneous coronary intervention (pPCI) is unclear. Objectives: To assess the effects of SGLT2is on myocardial fibrosis among patients with STEMI undergoing pPCI. Methods: Patients with STEMI undergoing pPCI with left ventricular ejection fraction ≤ 50% were randomized to dapagliflozin 10 mg or placebo. The primary endpoint was cardiac magnetic resonance (CMR)-derived 6-month changes in remote myocardium extracellular volume (ECV) fraction from baseline. Secondary endpoints included changes in CMR-derived myocardial volumes, change in serum fibrosis biomarker levels, and adverse events. Multivariable adjustment for infarction location and diabetes status was performed as sensitivity. The study was halted prematurely due to slow recruitment. Results: Fifty-two patients underwent randomization between May 2021 and April 2024 and completed follow-up. At 6 months, dapagliflozin resulted in a non-significant reduction in ECV change compared to placebo (−0.39 [4.7] vs. 1.43 [5.7]; difference: −1.82 [−4.86; 1.23]; p-value = 0.235) while also leding to a higher degree of reduction in N-terminal pro-peptide of type III collagen (−177.0 pg/mL [416.1] vs. 3.6 pg/mL [553.8]; p-value = 0.208). No significant differences in other biomarkers or adverse events were noted in the main analysis. After adjustment, dapagliflozin was associated with increased reduction in left ventricular end-systolic volume (−4.02 mL [7.4] vs. 0.10 mL [10.1]; difference: −4.92 [−9.8; −0.1]; p-value = 0.047). Conclusions: In STEMI patients undergoing pPCI, dapagliflozin did not result in a significant reduction in ECV or biomarkers of fibrosis at 6 months.

Background: Early neuroprognostication in Out‐of‐Hospital Cardiac Arrest (OHCA) remains challenging due to the lack of reliable biomarkers. Circulating microRNAs have emerged as potential indicators of inflammation and brain injury (HIBI). This study aimed to evaluate whether in silico‐predicted microRNAs could discriminate neurological outcomes early in OHCA patients. Methods: Consecutive OHCA patients admitted to the Acute Cardiac Care Unit with available cryopreserved blood samples were analysed. Neurological outcome was classified into favourable (Cerebral Performance Category (CPC) 1–2) and unfavourable (CPC 3–5). Blood samples at 0, 24, 72 h after hospital admission were collected. An in silico‐derived network of inflammation‐HIBI‐related microRNA was generated and validated in all patients at the three time‐points. Results: A total of 100 patients were included (59.7 ± 12.5 years, 19% women). 53% had unfavourable neurological outcomes. Eleven candidate microRNAs were identified, showing differential time‐dependent expression within 72 h. The earlier and most predictive microRNAs for unfavourable neurological outcome were miR‐1‐3p (AUC 0.637) and miR‐124‐3p (AUC 0.606) at 0 h, miR‐21‐5p (AUC 0.614) and miR‐499a‐5p (AUC 0.645) at 24 h. The miR‐499‐5p maintained the best AUC across all time‐points. A multiparametric model achieved an AUC of 0.690. A pro‐inflammatory environment, characterised by C‐Reactive Protein (CRP) and neutrophil‐to‐lymphocyte ratio, showed distinct temporal expression patterns regarding neurological outcome. Neuroinflammatory miR‐let‐7a‐5p, miR‐23a‐3p and miR‐146a‐5p were significantly overexpressed in the unfavourable group and correlated positively with CRP. Conclusions: In silico derived inflammatory and HIBI‐related microRNAs showed time‐dependent expression patterns that may distinguish neurological outcomes within 72 h after OHCA.