An exaggerated exercise pressor reflex (EPR) is associated with excessive sympatho-excitation and exercise intolerance in the chronic heart failure (CHF) state. We hypothesized that brain-derived neurotrophic factor (BDNF) causes the exaggerated EPR via sensitizing muscle mechanosensitive afferents in CHF. Increased BDNF expression was observed in lumbar dorsal root ganglia (DRGs) from CHF rats compared to sham rats. Immunofluorescence data showed a greater increase in the number of BDNF-positive neurons in medium and large-sized DRG subpopulations from CHF rats. Patch clamp data showed that incubation with BDNF for 4–6 h, significantly decreased the current threshold-inducing action potential (AP), threshold potential and the number of APs during current injection in Dil-labeled isolectin B4 (IB4)-negative medium-sized DRG neurons (mainly mechano-sensitive) from sham rats. Compared to sham rats, CHF rats exhibited an increased number of APs during current injection in the same DRG subpopulation, which was significantly attenuated by 4-h incubation with anti-BDNF. Finally, chronic epidural delivery of anti-BDNF attenuated the exaggerated pressor response to either static contraction or passive stretch in CHF rats whereas this intervention had no effect on the pressor response to hindlimb arterial injection of capsaicin. These data suggest that increased BDNF in lumbar DRGs contributes to the exaggerated EPR in CHF.

Etomidate is commonly used to induce anesthesia in cardiac surgery patients due to its favorable cardiovascular profile. Sedative-hypnotic effects are mediated by gammaaminobutyric acid (GABA) receptor complexes in the central nervous system. There are numerous studies in which etomidate and other drugs are compared in terms of their clinical outcomes. The relative efficacy and safety of etomidate, however, remains inconclusive. In this study, we performed a systematic analysis of randomized controlled trials to assess the impact of etomidate, on patients undergoing cardiac surgery, with respect to patient outcome and adverse events. A systematic review was conducted of all existing clinical trials exploring the safety and efficacy of etomidate in patients undergoing cardiac surgery. Randomized controlled trials (RCTs) that compared etomidate with other drugs during induction in adult cardiac surgery assessing hemodynamic parameters and clinical outcomes were included, while studies involving non-cardiac or pediatric surgery and those lacking relevant outcome data were excluded. Primary outcomes were all-cause 30-day mortality. Secondary outcomes included duration of tracheal intubation, duration of intensive care unit (ICU) stay, duration of hospital stay, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR) and other hemodynamic parameters, vasopressor requirements after induction and intubation, cortisol levels, and incidence of myoclonus. Sixteen randomized controlled trials involving 1162 patients were included. Etomidate did not affect the all-cause 30-day mortality of patients undergoing cardiac surgery compared to comparator drugs (RR, 0.96; 95 % CI, 0.26 to 3.49; P = 0.95). There were no significant differences in the duration of tracheal intubation (MD, -0.08 h; 95 % CI, -1.96 to 1.81; P = 0.94), the duration of ICU stay (MD, -2.07 h; 95 % CI, -8.09 to 3.96; P = 0.50) or the duration of hospital stay (MD, -0.62 d; 95 % CI, -2.25 to 1.00; P = 0.45) when etomidate was compared to comparator drugs. Patients receiving etomidate demonstrated a more stable hemodynamic profile after induction and intubation compared to those receiving comparator drugs. The requirement of a vasopressor after induction and intubation was significantly reduced with etomidate compared with those with comparator drugs (RR, 0.37; 95 % CI, 0.25 to 0.56; P < 0.00001). This systematic meta-analysis found a significant heterogeneity among included studies. In addition, most studies focused only on the hemodynamic profile of etomidate. Thus, efficacy and safety of etomidate could not be answered within this context. Nevertheless, for patients undergoing cardiac surgery, etomidate seems to offer a minimal beneficial cardiovascular profile in comparison with other agents during induction and intubation. However, improved hemodynamics did not improve clinical outcomes as Etomidate did not affect mortality, duration of tracheal intubation, the length of stay in ICU and hospital. Finally, infectious side effects as one important trigger for increased mortality in ICU patients due to the use of Etomidate could not be analyzed as data were mostly missing.

Background and Aims: Extracellular vesicles (EVs) are nanoscale carriers, including exosomes, microvesicles, and apoptotic bodies, that mediate intercellular communication by transporting proteins, nucleic acids, lipids, and metabolites. They regulate immunity, tissue repair, and cell differentiation. Increasing evidence highlights their dual roles in disease, where they may promote tumor growth and immune evasion but also serve as diagnostic and therapeutic tools. This review synthesizes advances in EV biology, their roles in health and disease, and their therapeutic potential. Methods: We conducted a narrative review of recent literature, focusing on EV isolation methods, biological functions, and clinical applications. Sources were selected to capture both mechanistic insights and translational perspectives. Results: Advances in isolation technologies, from ultracentrifugation to microfluidics, have improved the precision of EV characterization. EVs exhibit distinct molecular signatures, positioning them as promising biomarkers in cancer, cardiovascular, neurodegenerative, autoimmune, and infectious diseases. Mechanistic studies demonstrate their roles in immune modulation, tissue remodeling, and regeneration. As therapeutic agents, EVs show promise as drug delivery systems and as platforms for gene and immunotherapies, offering enhanced targeting and reduced toxicity compared to synthetic nanoparticles. Engineered EVs and hybrid EV–liposome systems further expand their applications, though challenges persist in scalability, standardization, and safety. Conclusion: EVs are central mediators of intercellular communication with transformative potential in diagnostics and therapeutics. Their biological properties position them as valuable biomarkers and delivery vehicles in precision medicine. Overcoming translational challenges, such as immunogenicity, oncogenic risks, and manufacturing limitations, will be essential for their successful clinical integration.

The cardio-renal syndrome (CRS) type 2 is defined as a progressive loss of renal function following a primary insult to the myocardium that may be either acute or chronic but is accompanied by a decline in myocardial pump performance. The treatment of patients with CRS is difficult, and the disease often progresses to end-stage renal disease that is refractory to conventional therapy. While a good deal of information is known concerning renal injury in the CRS, less is understood about how reflex control of renal sympathetic nerve activity affects this syndrome. In this review, we provide insight into the role of the renal nerves, both from the afferent or sensory side and from the efferent side, in mediating renal dysfunction in CRS. We discuss how interventions such as renal denervation and abrogation of systemic reflexes may be used to alleviate renal dysfunction in the setting of chronic heart failure. We specifically focus on a novel cardiac sensory reflex that is sensitized in heart failure and activates the sympathetic nervous system, especially outflow to the kidney. This so-called Cardiac Sympathetic Afferent Reflex (CSAR) can be ablated using the potent neurotoxin resinferitoxin due to the high expression of Transient Receptor Potential Vanilloid 1 (TRPV1) receptors. Following ablation of the CSAR, several markers of renal dysfunction are reversed in the post-myocardial infarction heart failure state. This review puts forth the novel idea of neuromodulation at the cardiac level in the treatment of CRS Type 2.

Acute lung injury (ALI) is associated with cytokine release, pulmonary edema and in the longer term, fibrosis. A severe cytokine storm and pulmonary pathology can cause respiratory failure due to acute respiratory distress syndrome (ARDS), which is one of the major causes of mortality associated with ALI. In this study, we aimed to determine a novel neural component through cardiopulmonary spinal afferents that mediates lung pathology during ALI/ARDS. We ablated cardiopulmonary spinal afferents through either epidural T1-T4 dorsal root ganglia (DRG) application or intra-stellate ganglia delivery of a selective afferent neurotoxin, resiniferatoxin (RTX) in rats 3 days post bleomycin-induced lung injury. Our data showed that both epidural and intra-stellate ganglia injection of RTX significantly reduced plasma extravasation and reduced the level of lung pro-inflammatory cytokines providing proof of principle that cardiopulmonary spinal afferents are involved in lung pathology post ALI. Considering the translational potential of stellate ganglia delivery of RTX, we further examined the effects of stellate RTX on blood gas exchange and lung edema in the ALI rat model. Our data suggest that intra-stellate ganglia injection of RTX improved pO ₂ and blood acidosis 7 days post ALI. It also reduced wet lung weight in bleomycin treated rats, indicating a reduction in lung edema. Taken together, this study suggests that cardiopulmonary spinal afferents play a critical role in lung inflammation and edema post ALI. This study shows the translational potential for ganglionic administration of RTX in ARDS.

Nitric oxide (NO) is a central regulator of cardiovascular function, influencing vascular tone, platelet activity, and inflammatory signaling. Despite decades of work defining its molecular pathways, translation into consistent clinical application has remained uneven, with findings across experimental, biomarker, and therapeutic studies often appearing inconsistent. Part of this variability reflects how NO behaves under different biological conditions. Its effects are shaped by where it is produced, how much is generated, and the biochemical environment in which it operates. Under some conditions, NO supports vascular homeostasis, while in others it contributes to oxidative and nitrosative stress, a pattern we refer to as the nitric oxide paradox. This review revisits commonly used NO-related biomarkers, including nitrate/nitrite (NOx), asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine, and considers why their clinical interpretation remains inconsistent. It also examines the limitations of NO-based therapies, where short half-life, systemic exposure, and limited control over delivery continue to constrain outcomes. Rather than viewing these findings as conflicting, this article considers them as reflections of how NO signaling shifts across different physiological contexts. We organize NO signaling according to four interacting determinants: enzymatic source, magnitude and duration of production, cellular compartment, and the surrounding redox environment. Framing NO biology in this way may help explain variability in both diagnostic and therapeutic settings and clarify where current approaches remain limited.