Search Results (561)

Regenerative medicine is increasingly leveraging the synergies between bioinspired conductive biomaterials and 3D/4D bioprinting to replicate the native electroactive and hierarchical microenvironments essential for functional tissue restoration. However, a critical gap remains in the intelligent integration of these technologies to achieve dynamic, responsive tissue regeneration. This review introduces a “bioinspired material–printing–function” triad framework to systematically synthesize recent advances in: (1) tunable conductive materials (polymers, carbon-based systems, metals, MXenes) designed to mimic the electrophysiological properties of native tissues; (2) advanced 3D/4D printing technologies (vat photopolymerization, extrusion, inkjet, and emerging modalities) enabling the fabrication of biomimetic architectures; and (3) functional applications in neural, cardiac, and musculoskeletal tissue engineering. We highlight how bioinspired conductive scaffolds enhance electrophysiological behaviors—emulating natural processes such as promoting axon regeneration cardiomyocyte synchronization, and osteogenic mineralization. Crucially, we identify multi-material 4D bioprinting as a transformative bioinspired approach to overcome conductivity–degradation trade-offs and enable shape-adaptive, smart scaffolds that dynamically respond to physiological cues, mirroring the adaptive nature of living tissues. This work provides the first roadmap toward intelligent electroactive regeneration, shifting the paradigm from static implants to dynamic, biomimetic bioelectronic microenvironments. Future translation will require leveraging AI-driven bioinspired design and organ-on-a-chip validation to address challenges in vascularization, biosafety, and clinical scalability. Full article

Mitral valve prolapse (MVP) is generally associated with excellent long-term outcomes when MR is absent or mild. Nonetheless, a small proportion of patients exhibit a distinct arrhythmogenic susceptibility, characterized by complex ventricular ectopy, sustained ventricular arrhythmias (VAs), and in rare instances, sudden cardiac death (SCD). This subgroup—collectively referred to as arrhythmic MVP (AMVP)—has prompted renewed attention in identifying individuals at elevated risk. Among the structural alterations associated with MVP, mitral annular disjunction (MAD) has gained recognition as a major contributor to arrhythmic vulnerability, arising from the pathological separation of the posterior annulus from the adjacent ventricular muscle. Advances in multimodality imaging, including trans-thoracic echocardiography (TTE), cardiac magnetic resonance (CMR), and cardiac computed tomography (cCT), have significantly improved delineation of MAD and clarified its relationship to the broader MVP spectrum. Current evidence suggests that MVP, MAD, and AMVP should not be regarded as isolated conditions but as intersecting phenotypes within a shared pathological framework. In certain patients, especially those without established myocardial fibrosis, abnormal annular dynamics appear to constitute the primary arrhythmogenic driver and may diminish after surgical intervention. In others, persistent arrhythmias despite optimal repair reflect a fibrosis-based substrate. This review synthesizes contemporary insights into the anatomical, biomechanical, and electrophysiological interplay linking MVP, MAD, and ventricular arrhythmogenesis, emphasizing implications for imaging-based risk assessment and individualized surgical management strategies. Full article

Background: The objective of this work was to support the implementation of the European Health Technology Assessment Regulation (EU HTAR) and optimize performance of the evolving EU HTA system. Therefore, an inclusive multi-stakeholder framework of key performance indicators (KPI) for success measurement was developed. Methods: A modified Delphi-procedure was applied as follows: (1) development of a generic KPI pool at the Fall Convention 2024 of the European Access Academy (EAA); (2) review of initial pool and identification of additional KPIs; (3) development of prioritized KPIs covering patient, clinician, Health Technology Developer (HTD), and System/Member State (MS) perspectives, and (4) consolidation of the stakeholder-centric KPIs after EAA’s Spring Convention 2025. Results: Steps 1 and 2 of the Delphi procedure revealed 14 generic KPI domains. Steps 3 and 4 resulted in four prioritized KPIs for patients (patient input; utilization of patient-centric outcome measures; time to access; equity); six for clinicians (population/intervention/comparator/outcomes (PICO); addressing uncertainty; clinician involvement; transparency; equity and time to access); four for HTDs (PICO; joint scientific consultation (JSC) process; joint clinical assessment (JCA) process; time to national decision making); five from a system/MS perspective (PICO; learning and training the health system; reducing duplication; equity and time to access). The scope of, e.g., the PICO-related KPI, differed between stakeholder groups. Also, several KPIs intentionally reached beyond the remit of EU HTA as they are also dependent on MS-specific factors including national health systems and budgets. Discussion and Conclusions: The KPI framework developed here presents a step towards the generation of systematic multi-stakeholder evidence to support a successful implementation of the EU HTAR. The relevance of the identified stakeholder-centric KPIs is confirmed by their alignment with the Health System Goals suggested in the context of “Performance measurement for health improvement” by the World Health Organisation. Implementation of the framework, i.e., measurement of KPIs, is envisioned to provide evidence to inform the 2028 revision of the EU HTAR. Full article

Type-2 Diabetes Mellitus (T2DM) is related to cardiac arrhythmias. The stellate ganglion (SG), part of the sympathetic nervous system, regulates heart function. Within the SG, satellite glial cells (SGCs) have gap junction channels (Cx43). Increased Cx43 permeability induces SGC depolarization and activates the PKC-MAPK14-ADAM17 signaling pathway, releasing some endogenous factors that stimulate nearby cardiac postganglionic sympathetic neurons (CPSN). This study investigated the activation of the PKC-MAPK14-ADAM17 signaling pathway in T2DM SGs and SGCs as a novel mechanism of sympathetic overactivation. A total of 56 Sprague-Dawley rats were randomly assigned to sham and T2DM groups, and T2DM was induced using a high-fat diet combined with low-dose streptozotocin. Real-time RT-PCR, Western blot, and ELISA quantified mRNA/protein expression and enzymatic activity. The patch clamp technique assessed neuronal voltage-gated Ca²⁺ currents and action potentials, while electrophysiological recording measured cardiac sympathetic nerve activity (CSNA). T2DM rats exhibited marked upregulation of MAPK14, PKC-α, and ADAM17 mRNA/protein in the SG, alongside elevated enzymatic activities of PKC and ADAM17. T2DM also increased Ca²⁺ currents and neuronal excitability in the CPSN and induced the elevation of the CSNA. Upregulated PKC-MAPK-ADAM17 signaling in the SG might contribute to cardiac sympathetic overactivation in T2DM rats by enhancing the cell excitability of the CPSN. Full article

Hypoglycaemia in patients with type 1 diabetes mellitus (T1DM) remains a major clinical burden and, beyond its metabolic complications, can cause serious cardiac arrhythmias. Multiple mechanisms lead to different types of arrhythmias during hypoglycaemia. However, existing studies often involve mixed diabetes populations, small cohorts, or limited monitoring during nocturnal periods, leaving a critical gap in understanding the links between glucose fluctuations and arrhythmic events. This review provides an updated combination of experimental and clinical evidence describing how autonomic dysfunction and ionic imbalances lead to electrophysiological instability and structural remodelling of the myocardium during hypoglycaemia. Continuous glucose monitoring (CGM) combined with electrocardiographic or wearable rhythm tracking may enable early detection of glycemic and cardiac disturbances and help identify high-risk individuals. Future prospective studies using combined CGM–ECG monitoring, particularly during sleep, are essential to clarify the relationship between hypoglycaemia and arrhythmic events. Full article

Transient receptor potential vanilloid 1 (TRPV1) channels are critical mediators of cutaneous allergic inflammation, contributing to pruritus, erythema, and hypersensitivity in allergic skin disorders. Despite their therapeutic potential, clinically available TRPV1 inhibitors remain limited, leaving effective treatment options lacking. Here, we focused on a self-constructed virtual pentapeptide library and identified a highly selective TRPV1 inhibitor that demonstrated pronounced anti-allergic effects in human skin assays. Through structure-based virtual screening of approximately 200,000 peptide conformations, five candidate pentapeptides, especially P5 (DQKNC), exhibited the inhibition. Electrophysiological recordings showed that P5 inhibited TRPV1 currents with nanomolar potency, while exhibiting negligible effects on major cardiac and neuronal ion channels, highlighting its favorable selectivity and safety profile. In capsaicin-induced human skin hypersensitivity tests, topical P5 significantly reduced burning pain, erythema, and pruritus, with simultaneous application providing the most robust relief. These findings reveal a short peptide with strong TRPV1 selectivity and demonstrable efficacy in alleviating skin inflammation and allergic responses, supporting the notion that rationally designed pentapeptides may represent promising topical therapeutics for allergic skin disorders. Full article

Background: Ischemic heart disease is the primary contributor to global mortality. The QRS-T angle at the anterior aspect of the heart serves as a significant biomarker of the heterogeneity in myocardial repolarization and the electrophysiological instability of the cardiac myocytes. A wide frontal QRS-T angle is associated with proximal vascular disease, coexistence of three-vessel disease, and increased mortality. Hereby, we aimed to examine the relationship between collateral circulation and frontal QRS-T angle in patients with chronic total occlusion (CTO). Methods: A cohort comprising 120 patients (17 females, 14.1%) who received a diagnosis of chronic total occlusion (CTO) subsequent to the administration of coronary angiography conducted for the evaluation of stable angina pectoris was incorporated into the investigation. The electrocardiographs of the patients were evaluated in detail, and the frontal QRS-T angle was calculated. The patients were categorized into two groups: subjects exhibiting an increased frontal QRS-T angle (>110° for men, >90° for women) and those presenting with a normative frontal QRS-T angle. Coronary angiographies of the patients were analyzed, and coronary collateral circulation was classified according to Rentrop classification. Results: Serum albumin level (OR = 0.711, 95% CI 0.564–0.896; p = 0.004) and poor collateral flow (OR = 17.7, 95% CI 12.2–85.3; p < 0.001) were significant predictors of raised frontal QRS-T angle. Conclusions: The frontal QRS-T angle is a novel parameter that is more reliable, consistent, and less sensitive to miscalculation and misidentification than other conventional electrocardiographic myocardial repolarization parameters. Revealing the bad collateral relationship with the frontal QRS-T angle may enable physicians to take more stringent precautions and change the risk factors related to the increased QRS-T angle in advance. Full article

Background and Clinical Significance: Upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, is increasingly prescribed for autoimmune and inflammatory diseases. Although its therapeutic safety profile is well established, fatal intoxications have not been reported to date. Case Presentation: We describe the first fatal case of upadacitinib overdose in a 13-year-old girl. Following ingestion of approximately 600 mg (40 × 15 mg tablets Rinvoq^®), the patient presented with deep coma, profound bradycardia (~40 bpm) with third-degree atrioventricular block, conduction delay, hypotension, hypothermia, and metabolic acidosis. Laboratory tests showed hyperglycemia (17.8 mmol/L) and only minimal elevations in cardiac biomarkers (CK 57.03 U/L, CK-MB 30.64 U/L, troponin 0.003 ng/mL). Despite advanced resuscitation, the patient succumbed within a few hours. Forensic toxicology revealed extremely high concentrations of upadacitinib, 1.84 µg/mL (~1840 ng/mL) in blood and 70.3 µg/mL in gastric contents, far exceeding reported therapeutic plasma levels (Cmax 36.0 ± 8.8 ng/mL). This case establishes the first reported value for a lethal upadacitinib concentration in humans. The combination of conduction abnormalities, refractory shock, and minimal biomarker changes is consistent with an acute electrophysiological and hemodynamic collapse rather than myocardial infarction. Conclusions: The toxicity of upadacitinib in this case is characterized by profound central nervous system depression, severe cardiovascular (electrophysiological and hemodynamic) disturbances, and metabolic abnormalities (acidosis and hyperglycemia). These findings provide essential reference data for clinical and forensic toxicology, highlight the fatal potential of upadacitinib in overdose, and underscore the importance of secure medication storage and pharmacovigilance in households with adolescents. Full article

Objective: This study examined the clinical characteristics, management strategies, and outcomes of heart failure (HF) patients in the Lebanese population to address knowledge gaps regarding comorbidities, adherence to guideline-directed medical therapy, and mortality. Methods: The study included 835 patients aged 18 years or older who were hospitalized for HF at a tertiary center between January 2020 and December 2023. Data encompassed demographics, medical history, treatments, and all-cause mortality. Results: The median age was 70.0 years (IQR: 62.0–79.0), with males comprising 60.8%. The most common comorbidities were hypertension (84.2%), coronary artery disease (74.6%), diabetes mellitus (55.2%), and atrial fibrillation (33.4%). Males had more ICD (17.1% vs. 8.6%, p < 0.001) and CRT-D implants (8.9% vs. 3.7%, p = 0.004), and higher coronary artery disease frequency (78.3% vs. 68.8%; p = 0.002), whereas females had higher rates of atrial fibrillation (39.4% vs. 29.5%; p = 0.003). HF patients with reduced ejection fraction were the most common (56.4%), followed by HF with preserved ejection fraction (30.1%). HF with preserved ejection fraction had the highest rates of hypertension (89.6%) and atrial fibrillation (39.4%). Utilization of ARNI (β = −0.423, HR = 0.655, p = 0.041, 95% CI: 0.437–0.983) and SGLT2i (β = −0.432, HR = 0.649, p = 0.035, 95% CI: 0.435–0.969) were linked to 34.5% and 35.1% reductions in mortality risk, respectively. Conclusions: These results highlight the substantial burden of HF in Lebanon. Distinct demographic and clinical patterns were identified by gender and left ventricular ejection fraction groups. The findings underscore the need for population-specific screening, management strategies, and targeted interventions to improve HF outcomes. Full article

Urea transporter (UT) proteins are a group of membrane proteins specifically facilitating the transmembrane transport of urea, primarily divided into the UT-A and UT-B subfamilies. Early studies have predominantly focused on their pivotal roles in the mechanism of urine concentration in kidneys. Recently accumulating evidences suggest that UTs are also expressed in the cardiovascular system, particularly in cardiomyocytes and vascular endothelial cells, where they contribute to critical physiological processes such as regulation of cell volume homeostasis, modulation of nitric oxide production, control of myocardial electrophysiological properties, and adaptation to cardiac stress. Importantly, impairments or disruptions in UT activities have been increasingly associated with the pathogenesis and progression of multiple cardiovascular disorders, including hypertension, uremic cardiomyopathy, myocardial hypertrophy, heart failure, cardiac conduction disorders and atherosclerosis, which deepens the understanding of the role of urea metabolism as a key component in cardiovascular homeostasis. This brief review summarizes the distribution and physiological functions of UTs in the cardiovascular system, and evaluates the potential and existing challenges of targeting UTs as a novel therapeutic approach for cardiovascular diseases. Full article

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. Here, we investigated whether TRPM2 contributes to the atrial natriuretic peptide (ANP) response during β-adrenergic stimulation. We compared how male C57BL/6J wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice (8–12 weeks old) respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in WT atria and measured ADP-ribose (ADPr)-evoked currents and hydrogen peroxide (H₂O₂)-induced Ca²⁺ influx characteristic of TRPM2; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling. Full article

Background: Advances in pediatric electrophysiology have revolutionized cardiac care by offering patients treatments for increasingly complex cardiac rhythm and conduction disorders. However, despite these innovations, there are a number of potential complications that clinicians have to deal with. Case presentation: This clinical case study describes a rare complication in a child following pacemaker implantation, namely the appearance and accumulation of air in the pacemaker pocket. The child underwent multiple cardiac surgery for a complex congenital heart defect (CHD). Unfortunately, during surgical repair of a ventricular septal defect, the conduction pathways were disturbed. This caused second-degree atrioventricular block and required implantation of an epicardial pacemaker system. Heart block developed several days postoperatively and the child underwent a series of diagnostic tests and was successfully treated. Discussion: Pneumothorax and pneumomediastinum with air dissemination into the pacemaker pocket may develop postoperatively. But this a rare complication of pacemaker implantation, especially in children. This complication can cause pacemaker malfunction and be life-threatening. In the presented clinical case, the most likely cause was spontaneous pneumothorax expanding to the mediastinum and into the pacemaker pocket. Conclusions: Early identification of this complication will minimize the risk of pacemaker dysfunction and improve clinical outcomes. Full article

A critical obstacle in cardiac cell therapy is the unpredictable and poorly understood initial electrophysiological integration of grafted cardiomyocytes into the host tissue, a process that dictates therapeutic success and arrhythmic risk. Current models fail to capture the earliest stages of functional coupling formation. Here, we employed a tailored bioengineering platform, where single cardiomyocytes were stabilized on minimalist electrospun polycaprolactone (PCL) nanofibers, to model the “graft–host” interface and study the dynamics of excitation wave transmission in real-time. Using high-speed optical mapping enhanced by a custom SUPPORT neural network, we achieved the first quantitative insights into the efficiency of nascent intercellular contacts. We determined that within the first 3 h, these initial connections are 39–44 times less effective at conducting excitation than mature contacts within the native monolayer, explaining the observed partial (46%) synchronization of grafted cells. This work provides the first direct measurement of the functional deficit during the initial minutes and hours of graft integration. It establishes that simple, inert polymer fibers can act as a catalytic scaffold to enable this fundamental biological process, offering a powerful strategy to deconstruct and ultimately control the integration of engineered tissues (or cells) for safer cell therapies. Full article

Background: Thyroid dysfunction is a prevalent endocrine disorder with significant cardiovascular consequences, particularly through its effects on cardiac electrophysiology. Electrocardiography (ECG), as a widely available and cost-effective diagnostic tool, provides valuable insight into these alterations. This systematic review and meta-analysis aimed to evaluate the relationship between thyroid hormone imbalance and ECG parameters. Methods: A comprehensive search of PubMed, ScienceDirect, and Google Scholar identified 1099 studies, of which 121 underwent full-text analysis. Ultimately, 37 studies with complete datasets were included in the quantitative synthesis, encompassing 167,074 participants across overt hyperthyroidism, subclinical and overt hypothyroidism, and euthyroid control groups. Results: Meta-analysis revealed significant alterations in key electrophysiological markers. Overt hyperthyroidism was associated with QTc and Tp-e prolongation, consistent with increased repolarization heterogeneity and arrhythmic risk. In overt hypothyroidism, QTc and Tp-e intervals were also prolonged, accompanied by reduced heart rate variability, reflecting autonomic imbalance. Subclinical forms demonstrated more variable results, though trends toward conduction and repolarization disturbances were observed. Importantly, several studies indicated that levothyroxine therapy or surgical treatment normalized abnormal ECG findings, underscoring their reversible nature. Conclusions: These results highlight the strong association between thyroid hormone abnormalities and ECG alterations, which may serve as early markers of arrhythmic risk and sudden cardiac death. Incorporating ECG screening into thyroid disease management could improve early detection, risk stratification, and cardiovascular prevention strategies. Full article

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a robust platform for modelling inherited cardiac disorders. Comparative analysis of ion channel activity in patient-specific and isogenic control lines provides critical insights into the molecular mechanisms underlying channelopathies and arrhythmias. Atrial-specific hiPSC-CMs (hiPSC-aCMs) exhibit distinct electrophysiological properties governed by unique ion channel expression profiles, underscoring the need for optimized methodologies to record atrial ionic currents accurately. Here, we characterized the electrophysiological features of hiPSC-aCMs using the Nanion Patchliner automated patch-clamp system. An optimized cell dissociation protocol was developed to enhance cell integrity and seal formation, while tailored intra- and extracellular solutions were employed to isolate specific ionic currents. Using this approach, we reliably recorded major atrial currents, including the sodium current (I_Na), L-type calcium current (I_CaL), transient outward potassium current (I_to), ultrarapid component of the delayed rectifier current (I_Kur), small-conductance calcium-activated potassium current (I_SK), and pacemaker funny current (I_f). The resulting current profiles were reproducible and consistent with those observed in native atrial cardiomyocytes. These findings establish the feasibility of the automated electrophysiological characterization of ion channels in hiPSC-aCMs. This platform enables more efficient investigation of pathogenic variants and facilitates the development of targeted therapeutics for atrial arrhythmias and related channelopathies. Full article