Search Results (37,196)

Background: High-density lipoproteins (HDL) exert protective effects on the endothelium, which are impaired in type 2 diabetes (T2D). Although monocyte-derived multipotential cells (MOMCs) can be differentiated into the endothelial lineage, it remains unclear whether HDL glycation, size, and composition could affect MOMCs differentiation. Methods: Twenty normoglycemic (49 years, 35% male), 20 prediabetic (52 years, 35% male), and 20 newly diagnosed T2D participants (51 years, 50% male) were recruited. HDL were isolated from each study group. The size, composition, and early, intermediate, or advanced glycation products of HDL were determined. CD14+ MOMCs were isolated from healthy volunteers and incubated with HDL from each group. Endothelial phenotypic expression was assessed by CD14⁺/KDR⁺ expression. Results: Compared with normoglycemic and prediabetic individuals, T2D patients had higher concentrations of early (4.4, 4.6, vs. 5.2 µmol/mg of protein, respectively; p = 0.049) and advanced (7.7, 8.7, vs. 14.3 µg-BSA-AGEs/mg of protein, respectively; p < 0.02) glycation products in HDL. HDL composition was similar among groups. The CD14+/KDR+ expression in MOMCs incubated with HDL from T2D patients was lower than that observed in prediabetes and normoglycemic individuals (46% vs. 52% and 61%, respectively; p = 0.002). Advanced glycation end products in HDL inversely correlated with CD14+/KDR+ cells (r = −0.418, p = 0.002), adjusting for other HDL characteristics. Conclusions: In T2D patients, increased HDL-advanced glycation impairs the endothelial phenotypic expression of MOMCs, independently of other HDL characteristics. Since advanced glycation leads to greater biological damage, these findings highlight the importance of preserving HDL integrity in T2D patients to support endothelial repair and potentially delay vascular complications. Full article

Postharvest dehydration is a major determinant of cucumber freshness and marketability, yet early reductions in internal water status are difficult to detect using conventional quality assessment methods. This study presents a non-destructive, physiology-informed deep learning approach that links cucumber surface color and texture patterns to internal hydration level for automated freshness classification. A time-resolved dataset comprising 4160 RGB images of cucumber fruits was paired with gravimetrically determined relative water content (RWC), used as an objective indicator of internal hydration status. Based on RWC, fruits were classified into four freshness categories: Very Fresh (≥98%), Moderately Fresh (95–98%), Low Freshness (90–95%), and Spoiled (<90%). A custom convolutional neural network (CNN) was trained using standardized RGB images and evaluated on an independent test set. The model achieved an overall classification accuracy of 91.35% and a Cohen’s Kappa coefficient of 0.875, indicating strong agreement between predicted and actual freshness classes. Classification performance was highest for the extreme freshness states, with F1-scores exceeding 0.94 for Very Fresh and Spoiled fruits, while intermediate classes showed greater overlap, reflecting the gradual nature of postharvest water loss. Model interpretability analyses revealed that the CNN consistently focused on physiologically meaningful surface color and texture features associated with dehydration. Overall, these findings highlight the potential of physiology-informed deep learning to advance non-destructive freshness assessment in cucumbers, offering a realistic pathway toward hydration-based sorting, improved shelf-life management, and intelligent quality monitoring in modern postharvest supply chains. Full article

Background: Chronic cocaine exposure is increasingly associated with persistent brain alterations, yet it remains unclear whether these changes reflect reversible neuroadaptation, accelerated brain ageing, or a degeneration-like trajectory in a vulnerable subgroup. This Perspective proposes a neuroprogressive vulnerability framework—referred to as cocaine-specific encephalopathy/cerebropathy only in a heuristic sense—to organise heterogeneous evidence without implying a distinct neurodegenerative disease entity. Methods: We conducted a structured, critical synthesis of peer-reviewed human and preclinical literature (PubMed, Scopus, Web of Science; inception to December 2025), integrating neuroimaging (MRI/DTI/fMRI/PET/SPECT), neuropathology/post-mortem findings, neurochemical and molecular mechanisms, and neuropsychological outcomes, with explicit attention to confounders (polysubstance use, psychiatric and medical comorbidity, HIV, vascular risk, abstinence duration). Results: Convergent evidence supports a multi-hit vulnerability model in which chronic stimulant exposure may weaken neural resilience through dopaminergic dysregulation, oxidative stress, mitochondrial dysfunction, neuroinflammatory signalling, and putative α-synuclein–related mechanisms. Human imaging studies consistently implicate fronto–striato–limbic circuits and suggest possible cerebellar involvement, but findings are heterogeneous and often cross-sectional; direct evidence of progressive neuronal loss or disease-defining proteinopathies attributable to cocaine remains limited. Conclusions: Rather than asserting cocaine-induced classic neurodegeneration, we outline an exploratory framework in which chronic cocaine exposure may increase susceptibility to neuroprogressive impairment in a subset of biologically vulnerable individuals. Longitudinal multimodal studies combining advanced imaging, biomarkers, and phenotypic stratification are needed to clarify causality, temporal progression, and reversibility with sustained abstinence. Full article

Natural killer (NK) cells, key effectors of innate immunity, are classically categorized into CD56^dim and CD56^bright subsets in humans. While murine NK cell heterogeneity has become increasingly recognized, the classification of mature NK cell subsets remains incompletely defined. Here, we comprehensively characterized CD127⁺ NK cells in mice and identified them as a distinct, mature subset, developing independently of the thymus and interleukin (IL)-15 signaling. Flow cytometric analyses revealed that CD127⁺ NK cells are broadly distributed across lymphoid and non-lymphoid tissues—including in C57BL/6 wild-type and athymic Foxn1^−/− mice—and exhibit a surface phenotype distinct from CD127⁻ NK and thymus-derived CD127⁺ NK cells. Functional assays demonstrated that CD127⁺ NK cells produce interferon-γ and exert cytotoxic activity, despite expressing markers typically associated with immature NK cells. CD127⁺ NK cells were absent in IL-7Rα^−/− mice but present in IL-15^−/− and IL-15Rα^−/− mice, indicating a selective dependence on IL-7 signaling. IL-7 promoted their proliferation and activation both in vitro and in vivo. These findings revise current models of NK cell development by identifying a novel, IL-7-responsive, IL-15-independent, thymus-independent, and functionally competent CD127⁺ NK cell subset that is phenotypically distinct from helper-like innate lymphoid cells (ILCs). This study provides a framework for future investigations on NK cell heterogeneity, tissue specialization, and cytokine-mediated regulation. Full article

Sepsis is characterized by dysregulated immune responses induced by damage-associated molecular patterns, such as extracellular cold-inducible RNA-binding protein (eCIRP), that frequently lead to acute lung injury (ALI) and high mortality. Recently, a subset of CD4⁺ T cells possessing both T helper 1 (Th1) and regulatory T cell (Treg) phenotypes, termed Th1-Treg cells, has been identified; however, their function in sepsis remains unknown. In this study, we investigated the dynamics, induction mechanisms, and functional roles of Th1-Treg cells in the development of sepsis-induced ALI. Polymicrobial sepsis was induced in mice using cecal ligation and puncture. In vivo, Th1-Treg cell accumulation in the lungs was analyzed in WT and CIRP^−/− mice following sepsis. In vitro, isolated CD4⁺ T cells from WT and TLR4^−/− mice were treated with eCIRP to evaluate Th1-Treg cell differentiation and downstream signaling pathways. STAT1 and STAT5 activation were evaluated, and pharmacological inhibitors were used to assess their involvement. Adoptive transfer of Th1-Treg cells was conducted to determine their functional impact on ALI and mortality in septic mice. We observed a significant accumulation of Th1-Treg cells in the lungs of WT septic mice compared to sham mice. eCIRP drove the induction of Th1-Treg cells in vitro, and CIRP^−/− mice exhibited decreased Th1-Treg cell accumulation in the lungs compared to WT mice after sepsis. In parallel to Th1-Treg cell induction, eCIRP activated signal transducer and activator of transcription, STAT1 and STAT5. Both the induction of Th1-Treg cells and the activation of STAT1/5 proteins were significantly attenuated in TLR4^−/− mice. Furthermore, pharmacological inhibition of STAT1/5 signaling significantly reduced eCIRP-induced Th1-Treg cell differentiation. Intriguingly, adoptive transfer of Th1-Treg cells significantly exacerbated ALI, resulting in increased mortality in sepsis. Our findings indicate Th1-Treg cells induced by the eCIRP–TLR4–STAT1/5 axis aggravate ALI, worsening mortality in sepsis. Targeting these pathogenic cells potentially alleviates sepsis-induced ALI. Full article

Disruption of circadian rhythms caused by constant artificial lighting (“light pollution”) is a significant risk factor for the development of metabolic and age-associated pathologies. The liver, as a central metabolic organ with pronounced circadian regulation of its functions, is particularly vulnerable to desynchronosis. The aim of this study was to evaluate the effect of three-month dark deprivation (constant lighting) and the corrective action of exogenous melatonin on the morphofunctional state of the liver in young mature rats. The experiment used 3-month-old male Wistar rats, divided into groups: control (standard light:dark cycle 10:14 h), dark deprivation group (DD, constant lighting 24 h/day), and DD + Melatonin group (DD + Mel, dark deprivation with melatonin administered in drinking water at a dose of 12 mg/L). After 3 months (animal age 6 months), a comprehensive analysis was performed. It was shown that dark deprivation causes a profound (more than five-fold) suppression of plasma melatonin levels, which is accompanied by the formation of a pro-senescent and metabolically dysfunctional phenotype of the liver. This was manifested by the development of steatosis, an 18% increase in hepatocyte area, a 30% decrease in the proportion of binucleated hepatocytes, activation of cellular senescence markers (p16, p21) and stress markers (p53), and suppression of the expression of circadian transcription factors BMAL1 and CLOCK. At the ultrastructural level, lipofuscin accumulation, damage to mitochondria and the Golgi apparatus were noted. Biochemically, hyperglycemia, increased AST activity, hypoproteinemia, hypoalbuminemia, hypercholesterolemia, and hypertriglyceridemia were revealed. Administration of exogenous melatonin completely prevented the development of these disorders, normalizing hormone levels, morphology, ultrastructure, biochemical parameters, and the expression of key molecular markers. Thus, three-month dark deprivation induces complex pro-senescent remodeling and metabolic dysfunction of the liver, mediated by melatonin deficiency, while exogenous melatonin demonstrates a pronounced hepatoprotective and chronoprotective effect. Full article

Background/Objectives: Breast cancer is a heterogeneous and complex disease with significant individual differences in molecular immunophenotype, biological behavior, histopathological morphology, and response to chemotherapy. The presence of tumor-infiltrating lymphocytes (TILs) has gained considerable attention due to growing evidence of their involvement in therapeutic efficacy, particularly in the response to neoadjuvant chemotherapy (NACT). Different immune cell subsets’ frequency, location, and functional orientation vary substantially between tumor types and individuals with apparently identical cancers. Currently, next-generation sequencing (NGS) has provided key insights into the composition of the tumor microenvironment. Simultaneously, immunohistochemistry (IHC) of paraffin-embedded biopsies allows the visualization of marker proteins within the immune infiltrate, thereby enhancing our understanding of the role of immune cells in cancer therapy. Methods: This exploratory study evaluated immune cell tumor infiltration using NGS with immune cell deconvolution, as well as automated IHC on Tru-Cut biopsies from 57 patients with locally advanced breast cancer. Image analysis was performed using Qupath v0.6.0 software. The percentage of infiltrating CD4+ or CD8+ T cells was determined, along with the expression of the markers FoxP3, LAG3, CTLA4, PD1, and TIM-3. We aimed to gain insights into the tumor microenvironment and its influence on the response to NACT in patients with breast cancer. Results: Transcriptomic immune deconvolution approaches suggested that a biased cytotoxic tumor environment is linked to chemosensitivity. IHC assays of individual markers reveal that baseline immune cell abundance and individual checkpoint expression did not differ significantly across the response groups. However, the functional organization and coordination of the tumor immune microenvironment showed distinct associations with chemosensitivity. Conclusions: Features representing immune balance, such as CD8/CD4 ratio and T cell-contextualized metrics, emerged as candidate predictors of pathological response to NACT, outperforming molecular phenotype alone in this exploratory cohort. Full article

Diabetes is a pivotal risk factor for cardiovascular disease as well as microvascular complications, including retinopathy and nephropathy. Chronic hyperglycemia is a key player in linking diabetes with endothelial dysfunction which, in turn, contributes to cardiovascular disease. Indeed, hyperglycemia acts as a trigger for endothelial dysfunction, promoting a shift in the endothelium from a protective, anti-inflammatory state to a dysfunctional, injury-prone phenotype. A hyperglycemic environment triggers several pathogenetic mechanisms, including alterations in bioenergetics, production of advanced glycation end products, oxidative stress and mitochondrial dysfunction, all contributing to endothelial dysfunction. The activation of these pathophysiological mechanisms by hyperglycemia culminates in reduced nitric oxide production, as well as the induction of oxidative stress and inflammation, all of which are pivotal in impairing endothelial homeostasis and promoting cellular damage. Besides these classical mechanisms, there is growing attention on novel pathogenetic factors linking diabetic hyperglycemia with endothelial dysfunction, such as the ACE2 protein. The latter is emergeing for its potential to counter hyperglycemia-induced cellular damage through its vasoprotective and anti-inflammatory actions, making it a promising therapeutic target for tackling endothelial dysfunction. This review provides an overview of classical as well as emerging mechanisms underpinning the deleterious effects of diabetic hyperglycemia on endothelial dysfunction. In turn, understanding the molecular interconnections between hyperglycemia and endothelial dysfunction is crucial for developing novel strategies to restore endothelial homeostasis and mitigate diabetic vascular complications. Full article

Papillary thyroid cancer (PTC) is the most common endocrine malignancy with especially high incidence in Middle Eastern populations. While classical hereditary syndromes explain a minority of cases, the broader germline landscape of non-syndromic PTC remains unclear. whole-exome sequencing was performed on 245 unselected Saudi PTC patients to identify germline pathogenic or likely pathogenic variants (PVs/LPVs) in cancer predisposition genes. Clinical and molecular characteristics, and family history were integrated to assess phenotypic correlations. Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1. Four patients (36.4%) carried PVs/LPVs in canonical FA pathway genes; this increased to five patients (45.5%) when RAD50 was included. Two unrelated patients harbored the same STK11 variant (p.R304Q) without classical Peutz–Jeghers syndrome features. A TP53 hotspot mutation (p.R175H) was identified in a patient with a personal history of gastric cancer, a malignancy associated with Li–Fraumeni syndrome. Notably, the BRCA1 PV detected matches a known Saudi founder mutation in hereditary breast cancer, now observed in PTC. Most germline positive cases lacked syndromic manifestations, underscoring limitations of phenotype or family history-driven genetic testing strategies. These findings suggest that a small subset of non-syndromic PTC cases may carry germline PVs/LPVs in cancer predisposition genes, highlighting the need for broader genetic screening frameworks. Unbiased whole-exome analysis in unselected cohorts can uncover under-recognized genetic risk and guide screening strategies to address the unique hereditary landscape of thyroid cancer in underrepresented populations. Full article

Background: Anorexia nervosa (AN) is a severe eating disorder occurring most frequently in adolescence, characterized by a high prevalence of psychiatric comorbidity. Emotional dysregulation (ED) refers to a transdiagnostic construct that often drives disordered eating behavior. The present study aimed to evaluate differences and similarities in the clinical presentation and response to treatment of young AN patients with high levels of ED (AN+ED) and with low levels of ED (AN−ED). Methods: A total of 40 female inpatients aged between 12 and 18 years were consecutively recruited and subdivided into two groups (AN+ED: n = 21; AN−ED: n = 19), based on the median of the subscale Affective Instability (AI) of the Reactivity, Intensity, Polarity and Stability questionnaire—youth version (RIPoSt-Y). At the recruitment (T0), and after 6 months (T1), the Body Mass Index (BMI) was calculated, and questionnaires and scales were administered to assess (a) the general functioning; (b) the severity of the eating disorder; and (c) the associated psychopathology. Results: At T0, an independent-samples t-test showed that the AN+ED group was characterized by a significantly greater impairment in clinical functioning and a greater severity of both the eating disorder and the associated psychopathology compared to the AN−ED group. At T1, the AN+ED group also showed significantly higher levels of cyclothymic, depressive, and anxious symptoms than the AN−ED group. Moreover, repeated-measures ANOVAs revealed a statistically marked improvement over time of the bulimic behaviors in the AN+ED group only. Conclusions: The present study underscored distinctive clinical features in AN patients with high and low levels of ED. Specifically, the AN+ED group was characterized by a most likely severe clinical phenotype that requires tailored intervention strategies. Full article

Retinoblastoma (Rb) is an intraocular tumor caused by genetic alterations in the RB1 and MYCN genes within developing retinal cells. Chemoresistance and metastasis are major challenges for treatment, with the bone marrow (BM) representing the most common metastatic site. We investigated the effect of tumor-derived sEVs (TDsEVs) on the crosstalk between metastatic site cells (BM-derived mesenchymal stem cells (BM-MSC)) and tumor cells, and characterized them according to MISEV guidelines. The uptake of sEVs and the associated phenotypic changes in the BM-MSCs were analyzed with confocal microcopy. The functional effects were assessed through MTT assays for viability, scratch and Transwell assays for migration, and colony- and sphere-formation assays to evaluate clonogenicity and self-renewal, while stemness marker expression was examined by immunoblotting. Secretome changes following sEV exposure were analyzed using dot blot assays. sEVs were taken up by both cells. TD-sEVs significantly enhanced BM-MSC migration and induced differentiation into a myofibroblast-like phenotype without affecting cell viability. Conversely, BM-MSC-derived sEVs promoted tumor cell viability, migration, and stemness marker expression. Both the BM-MSCs and tumor cells exhibited altered secretory profiles after sEV treatment. The in vitro findings provide cumulative evidence that sEV-mediated interactions contribute to a tumor-supportive milieu or premetastatic niche at the BM in Rb. Full article

Vascular ageing is a complex process marked by progressive endothelial dysfunction, chronic low-grade inflammation (“inflammageing”), and reduced regenerative capacity, driven in part by an imbalance between protective endothelial autophagy and cellular senescence characterized by a proinflammatory senescence-associated secretory phenotype (SASP). Disruption of this autophagy–senescence axis accelerates vascular inflammation, arterial stiffening, and atherogenesis. High-intensity interval training (HIIT), consisting of repeated bouts of near-maximal anaerobic effort with recovery periods, is widely used by both elite and recreational athletes and is increasingly recognized as an effective nonpharmacological strategy to enhance endothelial function, arterial elasticity, and mitochondrial biogenesis. However, excessively intense or poorly structured HIIT, particularly in the absence of adequate recovery or in individuals with underlying cardiometabolic or vascular vulnerability, may induce endothelial stress and promote maladaptive vascular remodelling, including calcification and plaque instability. These considerations underscore the need for refined individualized exercise prescription strategies that balance performance benefits with endothelial protection. Based on these observations, here, we introduce a novel conceptual framework, “shear dose–calibrated HIIT,” designed to understand and define an optimal shear dose capable of maximizing autophagic flux while minimizing SASP activation. Experimental and clinical evidence of HIIT-induced effects on flow-mediated dilation (FMD), pulse wave velocity (PWV), and redox biomarkers is presented, followed by the proposal of a biomarker panel for assessing autophagic flux and cellular senescence in peripheral samples (peripheral blood mononuclear cells (PBMCs), extracellular vehicles (EVs), and plasma). This integrative approach, which combines vascular mechanotransduction, redox biology, and autophagic signalling, provides a novel translational perspective on how individually calibrated HIIT can promote vascular longevity and reduce cardiometabolic risk associated with aging and metabolic syndrome. Full article

Background/Objectives: Endometrial cancer frequently develops resistance to therapy, partly due to the ability of tumor cells to adapt to cellular stress through non-apoptotic mechanisms. Mitochondrial dysfunction and cytoskeletal remodeling are increasingly recognized as key components of stress adaptation; however, their structural relationship under pharmacological stress in three-dimensional (3D) tumor models remains poorly characterized. The present study aimed to investigate the ultrastructural and phenotypic effects of lithium chloride (LiCl)-induced stress in 3D endometrial cancer spheroids, with a particular focus on mitochondrial alterations and intermediate filament organization. Methods: Three-dimensional spheroids generated from Ishikawa endometrial cancer cells were exposed to lithium chloride at concentrations of 1, 10, or 50 mM for defined time periods. Cell viability, proliferative activity, and clonogenic capacity were assessed using Trypan Blue exclusion, BrdU incorporation, and soft agar assays. Ultrastructural changes were examined by transmission electron microscopy to evaluate mitochondrial morphology, cytoplasmic organization, and intermediate filament distribution. Results: LiCl exposure resulted in a dose- and time-dependent reduction in cell viability, proliferation, and clonogenic potential in 3D spheroids. Ultrastructural analysis revealed pronounced mitochondrial swelling, cristae disorganization, and membrane-associated mitochondrial alterations. These changes were consistently accompanied by conspicuous accumulation and reorganization of intermediate filaments in close spatial proximity to damaged mitochondria, suggesting a structural association between cytoskeletal remodeling and mitochondrial injury. Across all experimental conditions, classical apoptotic ultrastructural features, including chromatin condensation and apoptotic body formation, were not observed. Conclusions: Together, these observations indicate that lithium chloride elicits a stress phenotype in 3D endometrial cancer spheroids that primarily manifests at the organelle and cytoskeletal levels, rather than through classical apoptotic execution. Although descriptive in nature, the present study highlights intermediate filament accumulation as a prominent structural feature of lithium-induced mitochondrial stress and establishes a structural reference point for future studies aimed at further investigating mitochondrial–cytoskeletal relationships during pharmacological stress in endometrial cancer. Full article

Background and Objectives: Chronic total occlusion (CTO) affects 30% of patients undergoing coronary angiography rendering poorer outcomes. While percutaneous coronary intervention (PCI) can be technically successful, RCTs show no survival benefit. Cardiovascular Magnetic Resonance (CMR) provides comprehensive myocardial phenotyping, offering prognostic insights in this high-risk cohort. Materials and Methods: Fifty-six patients with angiographically confirmed CTO underwent stress perfusion CMR with late gadolinium enhancement. Myocardial function, ischaemia and scar burden were quantified and compared across CTO territory and viability subgroups. Results: In patients with CTO, 27% of patients (15/56) had no viability. In patients with viable myocardium, 66% (27/41) demonstrated reversible ischaemia. Viable myocardium was associated with significantly higher LV stroke volumes (93.6 ± 20.1 mL vs. 80.9 ± 18.4 mL, p = 0.039), along with lower LV scar mass (18.7 ± 13.5g vs. 32.3 ± 12.8g; p = 0.002) and scar percentage (14.9 ± 8.3% vs. 25.9 ± 7.5%; p = 0.001). Viable myocardium showed more ischaemia both globally (11.6 ± 14.3g vs. 0.2 ± 9.3g; p = 0.005) and within the CTO territory (10.3 ± 10.3% vs. 2.3 ± 2.7%; p = 0.01). Non-viable myocardium was associated with significantly higher CTO-territory scar mass (9.4 ± 6.5 g vs. 5.1 ± 6.9 g; p = 0.046) and scar percentage (21.8 ± 13.3% vs. 11.7 ± 12.8%; p = 0.01), indicating extensive fibrosis. A scar burden threshold of 11.18% in CTO territory predicted non-viability with 80% sensitivity and 65.85% specificity (AUC = 0.701 [95% CI 0.54–0.87], p = 0.019). Conclusions: Among CTO patients, 27% harbour no viability, while patients with viable myocardium typically exhibit reversible ischaemia—representing a phenotype with preserved viability and inducible ischaemia. These findings support the use of multiparametric CMR to phenotype CTO territories prior to considering CTO-PCI. Full article

Background: Left ventriculo-arterial coupling (VAC) integrates the interaction between left ventricular contractility and the arterial system, representing a key determinant of cardiovascular efficiency. In rapidly changing hemodynamic states such as septic or cardiogenic shock, conventional indices of pressure or flow alone may be misleading. VAC provides a unified physiological framework to assess global cardiovascular performance and guide therapy. Objective: To review the physiological foundations, bedside assessment, and therapeutic applications of VAC in critically ill patients with rapidly fluctuating circulatory conditions. Methods and Content: The article revisits the underlying principles of VAC, expressed as the ratio between arterial elastance (Ea) and end-systolic elastance (Ees), and discusses their derivation from the pressure–volume relationship. Practical echocardiographic methods for bedside estimation, including the non-invasive single-beat approach, are outlined with illustrative figures. The review further examines how VAC patterns evolve in sepsis, cardiogenic shock, and heart failure and how this integrative index clarifies paradoxical responses to vasoactive and inotropic therapies. Specific therapeutic phenotypes are proposed according to Ea/Ees profiles, providing a structured approach to optimise coupling and restore circulatory efficiency. Summary: VAC offers a physiology-based perspective on cardiovascular performance, enabling clinicians to interpret complex hemodynamic changes beyond traditional measures of ejection fraction or mean arterial pressure. Its dynamic tracking may refine the assessment of therapeutic trajectories and improve bedside decision-making. Conclusions: By integrating ventricular and arterial function into a single measure, VAC bridges cardiovascular physiology and clinical practice. Its incorporation into routine critical care monitoring could enhance individualised hemodynamic management and serve as a foundation for future outcome-driven studies. Methodology: This narrative review was conducted using a structured literature search to ensure comprehensive coverage of contemporary evidence regarding ventriculo-arterial coupling (VAC) in critical care and shock states. A systematic search of PubMed/MEDLINE, Embase, and Scopus databases was performed from database inception through October 2025. The following key search terms were used: “ventriculo-arterial coupling”; “arterial elastance”; “end-systolic elastance”; “Ea/Ees”; “pressure–volume loops”; “septic shock”; “cardiogenic shock”; “critical care echocardiography”; “point-of-care ultrasound”; “mechanical circulatory support”. Reference lists of relevant articles, review papers, and consensus documents were also manually screened to identify additional pertinent studies. Only English-language publications were included. Both seminal foundational studies and recent contemporary investigations were reviewed to provide historical context and up-to-date clinical applicability. Full article