Search Results (952)

Background/Objectives: There is no consensus on standardized treatment algorithms for patients with acute ischemic stroke due to anterior circulation tandem occlusions. This study evaluated the outcomes of mechanical thrombectomy and carotid artery stenting in such patients, with a particular focus on a standardized, adaptive, and escalating antithrombotic strategy. Methods: This single-center retrospective study included patients with atherosclerotic tandem occlusion treated between January 2019 and July 2023 at our comprehensive stroke center. All patients underwent mechanical thrombectomy and carotid artery stenting and received a standardized antithrombotic regimen, including the administration of the GPIIb/IIIa antagonist eptifibatide as rescue therapy. Results: Sixty-seven patients were included in the analysis. Thirty-five patients (52.2%) received eptifibatide due to acute stent thrombosis. Subtotal to total revascularization (mTICI 2b-3) was achieved in 98.5% of patients. The carotid artery reocclusion rate was 3.4% at discharge. Symptomatic intracranial hemorrhage occurred more frequently in patients treated with eptifibatide (9.0% vs. 0%, p = 0.021) but was not associated with mortality or favorable outcome (mRS 0–2) at 90 days. In univariable regression analysis, eptifibatide administration was not significantly associated with symptomatic intracranial hemorrhage (OR 1.9, 95% CI 0.3–11.4; p = 0.465). Older age was associated with mortality. Conclusions: Our adaptive antithrombotic protocol demonstrated high revascularization and low carotid reocclusion rates. Rescue use of eptifibatide was not significantly associated with symptomatic intracranial hemorrhage; however, a clinically relevant risk cannot be excluded. These findings highlight the importance of tailored antithrombotic strategies in acute ischemic stroke to maintain stent patency while minimizing hemorrhagic complications. Full article

Mitral transcatheter edge-to-edge repair (M-TEER) has emerged as a cornerstone in the management of severe mitral regurgitation, serving as a robust, low-risk alternative to conventional mitral valve surgery. Although thromboembolic risk remains a critical clinical challenge, that varies significantly across the clinical continuum, from pre-procedural substrates to post-procedural management. This review highlights the role of atrial cardiomyopathy in creating a prothrombotic milieu even prior to intervention, while during the procedure, device time emerges as a potentially dominant independent predictor of embolic burden, marking the periprocedural window as the period of peak hazard. Furthermore, this article addresses the notable disparity between the near-universal presence of subclinical ischemic lesions on magnetic resonance imaging and the infrequent incidence of overt neurological deficits. As the post-procedural phase is considered, we discuss the shift from standardized antithrombotic protocols to individualized strategies and the potential role of concomitant left atrial appendage occlusion. Ultimately, integrating these stage-specific clinical and procedural determinants with emerging technologies—like digital twins and artificial intelligence—represents a promising frontier for mitigating embolic risks, optimizing procedural planning and patient safety in the evolving landscape of mitral valve interventions. Full article

Landmark epidemiological studies and clinical trials, such as the Seven Countries Study, the Lyon Diet Heart Study, the PREDIMED Study and the CORDIOPREV Study, have shown significant reductions in cardiovascular events in those following the Mediterranean diet (MD). The aim of the present work is to summarize the most robust available evidence and the major biological pathways underlying the protective effects of the MD, with particular emphasis on the role of PAF inhibitors. Mechanistically, MD functions through a complex synergy of antioxidant, anti-inflammatory, and antithrombotic effects that collectively improve lipid profiles, enhance endothelial function, optimize postprandial metabolism and cell membrane signaling, making it a functional model for human longevity. The PAF-Implicated Atherosclerosis Theory has emerged as a key unifying framework, proposing that Platelet-Activating Factor (PAF)—a highly potent lipid inflammatory mediator—plays a central role in the initiation and progression of atherosclerosis. Oxidized LDL promotes the production of PAF and PAF-like lipids, leading to endothelial dysfunction, vascular inflammation, and atherosclerotic plaque formation. Traditional Mediterranean foods are rich in natural PAF inhibitors, particularly the polar lipid fractions of extra virgin olive oil, as well as wine, fish, vegetables, onions, and garlic. Animal studies demonstrate that these compounds can reduce or even regress atherosclerotic lesions, independently of serum cholesterol levels. Human dietary interventions have further shown that MD-based meals and functional foods enriched with PAF inhibitors reduce PAF activity and improve thrombosis-related biomarkers. This mechanistic framework helps explain phenomena such as the “French Paradox” and the cardio-protective effects associated with fish consumption. Moreover, the extraction of PAF inhibitors from Mediterranean food by-products, such as olive pomace, offers promising ecological and economic advantages. Collectively, targeting PAF and increasing dietary intake of PAF inhibitors represent promising strategies for the prevention and management of atherosclerosis and other inflammatory diseases, supporting the view that PAF may function as a major, modifiable risk factor in these conditions. Full article

Background/Objectives: Early neurological deterioration (END) is a frequent and clinically relevant complication in patients with a single small subcortical infarction (SSI), including lacunar infarction and branch atheromatous disease (BAD). Despite initially mild symptoms, END occurs in approximately 20–25% of cases and is strongly associated with poor functional outcomes. However, definitions, mechanisms, predictors, and therapeutic strategies remain heterogeneous. This review aims to synthesize current evidence regarding the incidence, pathophysiology, predictors, and management of END in SSI. Methods: We performed a narrative review of published studies addressing END in patients with lacunar stroke or SSI. We analyzed data on END definitions and incidence, imaging and clinical predictors, proposed pathophysiological mechanisms, and preventive and rescue therapeutic strategies. Results: END definitions vary across studies, most commonly defined as a ≥2-point increase in the National Institutes of Health Stroke Scale within 48–72 h. Hemodynamic compromise due to proximal perforator pathology, particularly in BAD, appears central to END development. Advanced imaging studies demonstrate perfusion abnormalities beyond the infarct core, supporting the concept of a “lacunar penumbra.” Lesion topology, proximal infarct patterns, parent artery plaques, larger infarct size, and vertical extension are consistent imaging predictors. Clinical factors such as diabetes mellitus, higher baseline severity, systemic inflammation, and increased arterial stiffness further modulate risk. Preventive strategies, including early dual antiplatelet therapy and intensified antithrombotic regimens, show promising signals, while induced hypertension may benefit selected patients as a rescue therapy. However, evidence remains largely observational or derived from subgroup analyses. Conclusions: END in SSI is a multifactorial and potentially modifiable process driven by interactions between proximal vascular pathology, hemodynamic failure, and tissue vulnerability. Standardized definitions, MRI-based phenotyping, and mechanism-driven trials are needed to optimize risk stratification and develop targeted preventive and rescue strategies. Full article

Transcatheter structural heart interventions, including aortic, mitral and tricuspid valve replacement or repair, and patent foramen ovale, atrial septal defect, and left atrial appendage closure, have dramatically expanded over the past two decades, providing substantial improvements in both clinical outcomes and quality of life. These interventions are performed in a high-risk patient population, which is at risk for both thrombotic and bleeding complications. The introduction of prosthetic devices into the arterial or venous circulation under heterogeneous hemodynamic conditions inevitably increases the risk for thrombotic events and thromboembolic complications. Consequently, the selection of antithrombotic therapy (AT) regimen and its duration is complex and should be tailored to each patient’s risk profile, balancing the expected risk and benefits. This state-of-the-art review critically examines the thrombotic risks inherent to transcatheter structural heart interventions, synthesizes available evidence and current guidelines recommendations on antithrombotic management, and defines persisting gaps in knowledge while discussing the most relevant ongoing clinical trials. Full article

Background/Objectives: Non-variceal upper gastrointestinal bleeding (NVUGIB) remains a major clinical emergency, particularly among patients receiving antiplatelet or anticoagulant therapy, whose use has increased substantially in recent years. This study aimed to evaluate the clinical characteristics, endoscopic findings, risk stratification, and outcomes of NVUGIB in patients receiving antithrombotic therapy, and to compare the predictive performance of commonly used prognostic scores. Methods: This prospective cohort study included 89 patients receiving antithrombotic therapy who presented with NVUGIB at Beni-Suef University Hospitals between March 2023 and March 2025. Clinical presentation, laboratory findings, and endoscopic characteristics were recorded. Risk stratification was assessed using Glasgow–Blatchford (GBS), Rockall, Baylor, AIMS65, ABC, and PNED scores. The optimal cut-off values for prediction of rebleeding and mortality were determined using receiver operating characteristic (ROC) analysis and the Youden index. Area under the curve (AUC) values were reported with 95% confidence intervals. Results: Endoscopy revealed that peptic ulcers were the most common lesion (41/89, 46%), followed by erosive disease (27/89, 30%), with the stomach being the most frequently involved site (76.5%). Rebleeding occurred in 16 patients (18.0%), while mortality was observed in 2 patients (2.2%). The Glasgow–Blatchford score demonstrated the most consistent performance for predicting rebleeding, with an optimal cutoff value of 5.5 (derived using the Youden index), yielding 92.9% sensitivity and 78.8% specificity. For mortality prediction, AIMS65, ABC, and PNED scores showed very high AUC values, although these findings should be interpreted cautiously due to the small number of mortality events (n = 2). No statistically significant difference in rebleeding or mortality was observed between single and dual antithrombotic therapy, although patients receiving dual therapy required longer hospitalization and more transfusion units. Conclusions: In patients with antithrombotic-related GI bleeding, ulcers and erosions predominate, with minimal differences between single and dual therapy outcomes. Concomitant NSAID use trends toward higher mortality. Glasgow–Blatchford score offers optimal performance for both rebleeding and mortality prediction, with a cutoff of 5.5 providing excellent sensitivity (92.9%) and specificity (78.8%) for rebleeding risk assessment. Full article

Background/Objectives: Haemoadsorption has recently emerged as an extracorporeal treatment option for sepsis, septic shock, intoxications, and cardiac surgery to modulate dysregulated inflammatory responses or remove a wide range of circulating molecules. To ensure appropriate clinical use of the CytoSorb^® haemoadsorber, it is essential to understand the extent to which specific drugs are adsorbed by the device. Methods: We conducted a systematic literature review using the PubMed and Ovid MEDLINE database to identify studies on drug binding to the CytoSorb^® haemoadsorber, including both in vivo and in vitro studies. Publications in English language, available up to 31 December 2025 that reported or enabled calculation of percentage of drug removal, CytoSorb^® clearance or half-life during CytoSorb^® therapy were included. Records were screened, eligibility and quality were assessed, and data were extracted independently by two reviewers. Results: We found that 26 studies reported on the binding of 56 drugs to CytoSorb^®, with most available information relating to antibiotics used in the treatment of sepsis and septic shock. CytoSorb^® appears to remove vancomycin and linezolid but not meropenem, although data for other antibiotics are insufficient to assess clinical relevance. Data on the removal of anticoagulant and antithrombotic drugs with CytoSorb^® before and during cardiac surgery indicate that using this procedure to reduce complications associated with apixaban and ticagrelor is feasible and safe. The available evidence on the use of CytoSorb^® for drug poisoning is of very low quality. Conclusions: Although the number of studies on drug binding to the CytoSorb^® is increasing, the review is limited by the marked heterogeneity among the included studies. It is advised to use therapeutic drug monitoring whenever possible during CytoSorb^® treatment. Research of binding of drugs to CytoSorb^® is crucial for its safe and effective clinical use, but adequate methodology is necessary. Full article

Background: Lumboperitoneal (LP) shunt surgery is an established treatment for idiopathic normal pressure hydrocephalus (iNPH). In Japan, patients undergoing LP shunt surgery are often hospitalized for several days to more than one week after surgery, even in uncomplicated cases, reflecting concerns regarding early complications, cerebrospinal fluid overdrainage, and discharge readiness in older adults. This study evaluated the feasibility and short-term safety of a perioperative optimization pathway for planned short-stay hospitalization after LP shunt surgery. Methods: This single-center retrospective before-and-after cohort study included 15 consecutive patients who underwent elective LP shunt surgery. Six patients were managed using a conventional hospitalization pathway, whereas nine patients were treated under a short-stay pathway targeting discharge after one postoperative night. Key perioperative modifications included a uniform higher initial programmable valve pressure (level 7), structured discharge education, scheduled postoperative analgesia, waterproof wound sealing permitting early showering, and early outpatient follow-up with head computed tomography for staged valve pressure adjustment. The primary outcome was 30-day safety, defined as readmission, reoperation, or major postoperative complications. Results: Baseline characteristics were generally comparable between groups, although the short-stay group was slightly older and had more frequent antithrombotic therapy. Mean hospital length of stay was shorter in the short-stay group than in the conventional group (3.7 ± 2.0 vs. 9.7 ± 0.8 days; median, 3 vs. 9.5 days). Orthostatic headache requiring valve adjustment occurred in three conventional cases but in none of the short-stay patients. No patients in the short-stay group required readmission or reoperation within 30 days. Conclusions: In this pilot before-and-after study, a short-stay LP shunt pathway incorporating perioperative optimization and individualized discharge decision-making was feasible and was not associated with an apparent increase in early adverse events. These findings should be interpreted as exploratory and may support further evaluation of short-stay management strategies for selected patients undergoing LP shunt surgery in Japan. Full article

The clinical application of small-diameter vascular grafts (SDVGs; <6 mm) is limited by thrombosis and mediated by protein adsorption, platelet activation, and coagulation. To address this, we develop a dual-modified polycaprolactone (PCL) graft via covalent conjugation of bivalirudin (BV), a direct thrombin inhibitor, and aspirin (ASA), a cyclooxygenase-1 suppressor. Compared with pure PCL, the BV/ASA-modified PCL graft reduces bovine serum albumin adsorption by 35.7% and fibrinogen adsorption by 36.2%, while maintaining mechanical properties and structural integrity. Platelet adhesion, assessed by LDH viability, is reduced by 42.6%, and the blood clotting index (BCI) is increased by 67.4%, indicating enhanced anticoagulation. The modified surface enhances anticoagulation and exhibits cell viability above 80%, confirming non-toxicity. These in vitro results demonstrate that BV and ASA dual functionalization effectively improves the antithrombotic performance of PCL vascular grafts, suggesting its potential as a candidate for further preclinical evaluation in SDVG applications. Full article

Percutaneous left atrial appendage occlusion (LAAO) has become an established alternative to long-term oral anticoagulation for stroke prevention in patients with atrial fibrillation, with expanding indications beyond those with absolute contraindications to anticoagulation. Alongside its broader adoption, device-related thrombus (DRT) has emerged as a clinically relevant complication that directly compromises the protective intent of LAAO. This comprehensive narrative review synthesizes contemporary evidence on the incidence, mechanisms, predictors, clinical impact, and management of DRT. DRT is a multifactorial phenomenon that carries an annual incidence ranging from 1.75% to almost 5%, resulting from the interplay between post-implant flow dynamics, device engineering, endothelialization processes, procedural factors, and patient-specific prothrombotic features. Accumulating data from observational registries links DRT to increased risks of ischemic stroke, systemic embolism, major adverse cardiovascular events (MACE), and mortality. Although evidence is growing, optimal management regimens for both the prevention and treatment of DRT remain undefined. Moreover, a lack of standardization also affects diagnosis and imaging surveillance, mainly performed by transesophageal echocardiography or cardiac computed tomography. By integrating mechanistic insights, clinical predictors, device-specific considerations, and therapeutic evidence, this review highlights current knowledge gaps and proposes practical considerations to inform individualized risk stratification, surveillance, and management of DRT in contemporary LAAO practice. Full article

Diabetes mellitus (DM) is a complex metabolic disorder associated with a heightened risk of cardiovascular events, largely driven by a hypercoagulable and hypofibrinolytic state. The pathophysiological interplay between chronic hyperglycemia, oxidative stress, insulin resistance, and systemic inflammation fosters profound alterations in the coagulation cascade, endothelial function, and platelet activity. This narrative review synthesizes evidence from studies published between 2008 and 2026, focusing on coagulation and platelet-related biomarkers selected based on their biological relevance to thrombosis, endothelial dysfunction, and inflammation, as well as the availability of clinical and interventional data across different forms of DM. Although there are numerous biomarkers involved in the pathogenesis of various forms of diabetes, this narrative review critically examines key coagulation biomarkers—including D-dimer, fibrinogen, prothrombin, tissue thromboplastin or tissue factor, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, plasminogen activator inhibitor-1, von Willebrand factor, and β-thromboglobulin—across distinct diabetes subtypes, including type 1, type 2, gestational, and secondary forms linked to endocrinopathies and pancreatic diseases. The literature reveals substantial subtype-specific heterogeneity in hemostatic alterations. For instance, Type 1 DM is characterized by early endothelial dysfunction and platelet activation, while Type 2 DM presents with elevated coagulation factors, impaired fibrinolysis, and a proinflammatory milieu. Gestational DM exhibits pregnancy-specific changes in coagulation, yet distinguishing them from obesity-related effects remains challenging. Secondary diabetes forms, such as those associated with Cushing’s syndrome or pancreatitis, further underscore the diversity in thrombotic risk profiles. Among the coagulation and platelet activation biomarkers reviewed, fibrinogen, P-selectin, and plasminogen activator inhibitor-1 demonstrate the most consistent associations with glycemic control, vascular dysfunction, and therapeutic modulation, particularly in type 2 diabetes, suggesting greater potential for clinical translation. In contrast, evidence for markers such as D-dimer, tissue factor or tissue thromboplastin, and soluble urokinase plasminogen activator receptor remains heterogeneous and insufficient for routine clinical application. By synthesizing mechanistic insights and clinical data, this review highlights the urgent need for subtype-tailored coagulation assessment in diabetes management. A better understanding of the dynamic alterations in coagulation pathways may facilitate earlier detection of vascular complications and inform personalized antithrombotic strategies. Full article

Objective: To evaluate the prognostic utility of the five-item modified Frailty Index (mFI-5) for postoperative outcomes in older adults undergoing posterior lumbar interbody fusion (PLIF) for degenerative lumbar disease and to develop an interpretable preoperative risk model for medical complications (CxME). Methods: We retrospectively reviewed consecutive patients aged ≥65 years who underwent PLIF for lumbar spondylosis at a single tertiary institution. Baseline demographics, comorbidities, symptoms, American Society of Anesthesiologists (ASA) physical status, bone mineral density, antithrombotic use, perioperative laboratory findings, and operative variables were collected. CxME were defined as Clavien–Dindo grade ≥ II complications occurring during index hospitalization or within 30 days postoperatively. mFI-5 was calculated from five preoperative variables and stratified as 0, 1, and ≥2. Multivariable logistic regression was used to identify independent predictors of CxME. Results: Among 255 patients (mean age 72.6 years), 53 (20.8%) developed CxME. Patients with CxME were older and had higher rates of diabetes mellitus and preoperative dependency. mFI-5 ≥ 2 was more frequent in patients with CxME than in those without (66.0% vs. 27.3%, p < 0.001). Higher frailty was associated with older age, greater comorbidity burden, higher ASA class, lower preoperative hemoglobin, greater transfusion exposure, longer hospital stay, and a higher incidence of CxME (14.0%, 9.6%, and 38.9% for mFI-5 scores 0, 1, and ≥2, respectively; p < 0.001). In multivariable analysis, age (OR 1.133, 95% CI 1.055–1.216; p < 0.001) and mFI-5 (OR 2.103, 95% CI 1.387–3.188; p < 0.001) independently predicted CxME. The Age + mFI-5 model showed fair discrimination (optimism-corrected area under ROC 0.734). Conclusions: Preoperative frailty and age independently predicted postoperative medical complications after PLIF in older adults. The Age + mFI-5 model may support risk stratification, counselling, and perioperative optimization. Full article

Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein–kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies. Full article

Background: Contemporary coronary artery bypass grafting (CABG) is often performed in patients with diffuse atherosclerosis, severe calcification, prior percutaneous coronary intervention (PCI), and fragile myocardium, creating intraoperative scenarios that can compromise target selection, anastomotic quality, and completeness of revascularization. We synthesize operative strategies and outcomes across five predefined “complex CABG” scenarios. Methods: A focused literature review was performed targeting intraoperative CABG challenges in adult patients. Two reviewers independently screened titles/abstracts and selected studies describing operative details, technical considerations, or outcomes relevant to (1) intramyocardial/embedded coronaries, (2) severely calcified or diffuse disease requiring reconstruction, (3) small-caliber targets/flow-limited grafting, (4) iatrogenic right ventricular (RV) injury, and (5) failed PCI/stent-related surgical management. Disagreements were resolved through discussion and consensus. Results: Thirty core publications were synthesized across five complex intraoperative CABG scenarios (intramural/embedded coronaries n = 7; calcified/diffuse disease n = 7; small-caliber/flow-limited targets n = 7; iatrogenic RV injury n = 5; failed PCI/stent-related management n = 5). Intramural/embedded targets: reported intramyocardial LAD prevalence ranged from 2.2–13%, and studies emphasized structured localization strategies with a small but real risk of ventricular injury depending on technique. Severely calcified/diffuse disease: reconstructive approaches (endarterectomy, patch angioplasty, long-segment LAD reconstruction) were used to create graftable beds when standard anastomosis was not feasible, with series reporting acceptable early mortality and generally high early-to-midterm patency when paired with planned antithrombotic and imaging follow-up strategies. Small-caliber targets: vessel size alone did not preclude durable grafting when flow was optimized, with evidence supporting flow-augmenting designs (e.g., sequential grafting) and intraoperative flow verification to reduce low-flow failure in limited runoff beds. Iatrogenic RV injury: bailout techniques prioritized rapid hemostasis while preserving LAD/graft patency using buttressed closure concepts designed for constrained exposure and ongoing bleeding risk. Failed PCI/stent-related pathology: long stented segments shifted operative planning from distal target selection to target reconstruction (stentectomy/endarterectomy with long-segment LAD reconstruction), with angiographic follow-up cohorts demonstrating feasible revascularization but variable patency by territory and lesion extent. Conclusions: Complex CABG is best approached as structured, anatomy-driven problem-solving: deliberate target localization, creation of a graftable bed when needed, flow-augmenting graft design, and predefined bailout options. Standardized comparative studies are needed to define optimal strategies across these common clinically important scenarios. Full article

Whey is a major by-product of the dairy industry and represents a valuable source of proteins that can be enzymatically converted into bioactive peptides with diverse health-related functions. In recent years, increasing attention has been given to whey-derived peptides due to their antioxidant, antihypertensive, antimicrobial, anti-inflammatory, antithrombotic, immunomodulatory, and anticancer activities, highlighting their potential use as functional ingredients and nutraceutical compounds. The generation and biological functionality of these peptides are strongly influenced by the protein source, processing conditions, enzymatic or microbial hydrolysis strategies, and peptide structure. Unlike the existing literature, this review provides an analysis of individual peptide sequences, meticulously linking their specific chemical structures to their diverse biological activities, such as antioxidants, antihypertensive, and immunomodulatory effects. By moving beyond general protein hydrolysis, this work offers a unique comparative framework that evaluates how these distinct peptide fractions perform under industrial conditions. Furthermore, it bridges the gap between laboratory discovery and commercial implementation, focusing on critical parameters for large-scale production, stability in functional food matrices, and the regulatory pathways required for market-ready nutraceuticals. This integrated approach provides a strategic roadmap for translating molecular bioactivity into high-value industrial applications. This review provides an applied overview of recent advances in the production of whey bioactive peptides, emphasizing enzymatic generation methods, structure–activity relationships, and underlying mechanisms of action associated with their biological effects. In addition, current and emerging applications of whey-derived peptides in functional foods, nutraceuticals, and health-oriented formulations are critically discussed. Finally, key challenges related to peptide stability, bioavailability, industrial scalability, and regulatory aspects are addressed to identify future perspectives for the effective translation of whey bioactive peptides from research to practical applications. Full article