Self-Adapting Biomass Hydrogel Embodied with miRNA Immunoregulation and Long-Term Bacterial Eradiation for Synergistic Chronic Wound Therapy.

Chronic wound rescue is critical for diabetic patients but is challenging to achieve with a specific and long-term strategy. The prolonged bacterial inflammation is particularly prevalent in hyperglycemia-induced wounds, usually leading to severe tissue damage. Such a trend could further suffer from an environmental suitability provided by macrophages for persisting Staphylococcus aureus (S. aureus) and even deteriorate by their mutual reinforcement. However, the strategy of both suppressing bacteria growth and immunoreprogramming the inflammatory type of macrophages to break their vicious harm to wound healing is still lacking. Here, a self-adapting biomass carboxymethyl chitosan (CMC) hydrogel comprising immunomodulatory nanoparticles is reported to achieve Gram-negative/Gram-positive bacteria elimination and anti-inflammatory cytokines induction to ameliorate the cutaneous microenvironment. Mechanistically, antibacterial peptides and CMCs synergistically result in a long-term inhibition against methicillin-resistant S. aureus (MRSA) over a period of 7 days, and miR-301a reprograms the M2 macrophage via the PTEN/PI3Kγ/mTOR signaling pathway, consequently mitigating inflammation and promoting angiogenesis for diabetic wound healing in rats. In this vein, immunoregulatory hydrogel is a promising all-biomass dressing ensuring biocompatibility, providing a perspective to regenerate cutaneous damaged tissue, and repairing chronic wounds on skin.

Noninvasive neuromodulation protects against doxorubicin-induced cardiotoxicity and inhibits tumor growth.

Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tragus vagus nerve stimulation (tVNS) improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 312 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.

Sex Differences in Clinical Outcomes Associated With Quantitative Flow Ratio-Guided Percutaneous Coronary Intervention.

Background: FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) reported improved clinical outcomes in quantitative flow ratio (QFR) relative to angiography-guided percutaneous coronary intervention (PCI), but the clinical impact of QFR-guided PCI according to sex remains unknown. Objectives: The authors sought to compare sex differences in the 2-year clinical benefits of a QFR-guided PCI strategy and to evaluate the differences in outcomes between men and women undergoing contemporary PCI. Methods: This study involved a prespecified subgroup analysis of the FAVOR III China trial, in which women and men were randomized to a QFR-guided strategy or a standard angiography-guided strategy. Sex differences in clinical benefit of the QFR guidance were analyzed for major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction, or ischemia-driven revascularization within 2 years. Results: A total of 1,126 women and 2,699 men were eligible and the occurrence of 2-year MACE was similar between women and men (10.3% vs 10.5%; P = 0.96). Compared with an angiography-guided strategy, a QFR-guided strategy resulted in a 7.9% and 9.7% reduction in PCI rates in men and women, respectively. A QFR-guided strategy resulted in similar relative risk reductions for 2-year MACE in women (8.0% vs 12.7%; HR: 0.62; 95% CI: 0.42-0.90) and men (8.7% vs 12.4%; HR: 0.69; 95% CI: 0.54-0.87) (Pinteraction = 0.61). Furthermore, QFR values were not significantly different between men and women with various angiographic stenosis categories. Conclusions: A QFR-guided PCI strategy resulted in improved MACE in both men and women at 2 years compared with an angiography-guided PCI strategy. The FAVOR III China Study [FAVOR III China]; (NCT03656848).

Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

A Biomimetic Nociceptor Using Centrosymmetric Crystals for Machine Intelligence.

Pain sensation is a crucial aspect of perception in the body. Force-activated nociceptors encode electrochemical signals and yield multilevel information of pain, thus enabling smart feedback. Inspired by the natural template, multi-dimensional mechano-sensing materials provide promising approaches for biomimetic nociceptors in intelligent terminals. However, the reliance on non-centrosymmetric crystals has narrowed the range of these materials. Here centrosymmetric crystal Cr3+ -doped zinc gallogermanate (ZGGO:Cr) with multi-dimensional mechano-sensing is reported, eliminating the limitation of crystal structure. Under forces, ZGGO:Cr generates electrical signals imitating those of neuronal systems, and produces luminescence for spatial mapping of mechanical stimuli, suggesting a path toward bionic pain perception. On that basis, a wireless biomimetic nociceptor system is developed and a smart pain reflex in a robotic hand and robot-assisted biopsy surgery of rat and dog is achieved.

Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias.

BACKGROUND: Neural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases the incidence of ventricular arrhythmias (VAs). Interleukin-6 (IL-6) is an important factor of the neuroimmune interaction. OBJECTIVE: The present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. METHODS: Eighteen beagles were randomly allocated to a control group (saline with myocardial infarction [MI], n = 6), adeno-associated virus (AAV) group (AAV with MI, n = 6), and IL-6 group (overexpression of IL-6 via AAV vector with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into the LSG. LSG function and ventricular electrophysiology were assessed at 31 days after surgery, and a canine MI model was established. Samples of the LSG were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 patients with acute MI on the day after they underwent percutaneous coronary intervention to assess the correlation between IL-6 levels and SNA. RESULTS: IL-6 overexpression increased cardiac SNA and worsened postinfarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted expression of nerve growth factor, c-fos, and fos B in the LSG, and activated the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and heart rate variability frequency domain index as well as T-wave alternans. CONCLUSION: IL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway, elevating the risk of VA after MI.

Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

Efficacy of a WeChat-Based Multimodal Digital Transformation Management Model in New-Onset Mild to Moderate Hypertension: Randomized Clinical Trial.

BACKGROUND: The advantages of multimodal digitally transformed mobile health management for patients diagnosed with mild to moderate hypertension are not yet established. OBJECTIVE: We aim to evaluate the therapeutic benefits of a novel WeChat-based multimodal digital transforming management model in mobile health blood pressure (BP) management. METHODS: This randomized controlled clinical trial included 175 individuals with new-onset mild to moderate hypertension who were admitted to our center between September and October 2022. The patients were randomly assigned to either the multimodal intervention group (n=88) or the usual care group (n=87). The primary composite outcome was home and office BP differences after 6 months. The major secondary outcomes were 6-month quality-of-life scores, including the self-rating anxiety scale, self-rating depression scale, and Pittsburgh Sleep Quality Index. RESULTS: The mean home BP decreased from 151.74 (SD 8.02)/94.22 (SD 9.32) to 126.19 (SD 8.45)/82.28 (SD 9.26) mm Hg in the multimodal intervention group and from 150.78 (SD 7.87)/91.53 (SD 9.78) to 133.48 (SD 10.86)/84.45 (SD 9.19) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -8.25 mm Hg (95% CI -11.71 to -4.78 mm Hg; P<.001) and -4.85 mm Hg (95% CI -8.41 to -1.30 mm Hg; P=.008), respectively. The mean office BP decreased from 153.64 (SD 8.39)/93.56 (SD 8.45) to 127.81 (SD 8.04)/ 82.16 (SD 8.06) mm Hg in the multimodal intervention group and from 151.48 (SD 7.14)/(91.31 (SD 9.61) to 134.92 (SD 10.11)/85.09 (SD 8.26) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -9.27 mm Hg (95% CI -12.62 to -5.91 mm Hg; P<.001) and -5.18 mm Hg (95% CI -8.47 to -1.89 mm Hg; P=.002), respectively. From baseline to 6 months, home BP control <140/90 mm Hg was achieved in 64 (72.7%) patients in the multimodal intervention group and 46 (52.9%) patients in the usual care group (P=.007). Meanwhile, home BP control <130/80 mm Hg was achieved in 32 (36.4%) patients in the multimodal intervention group and 16 (18.4%) patients in the usual care group (P=.008). After 6 months, there were significant differences in the quality-of-life total and graded scores, including self-rating anxiety scale scores (P=.04), self-rating depression scale scores (P=.03), and Pittsburgh Sleep Quality Index scores (P<.001), in the multimodal intervention group compared with the usual care group. CONCLUSIONS: The WeChat-based multimodal intervention model improved the BP control rates and lowered the BP levels more than the usual care approach. The multimodal digital transforming management model for hypertension represents an emerging medical practice that utilizes the individual's various risk factor profiles for primary care and personalized therapy decision-making in patients with hypertension. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200063550; https://www.chictr.org.cn/showproj.html?proj=175816.

Interface-Engineered Field-Effect Transistor Electronic Devices for Biosensing.

Promising advances in molecular medicine have promoted the urgent requirement for reliable and sensitive diagnostic tools. Electronic biosensing devices based on field-effect transistors (FETs) exhibit a wide range of benefits, including rapid and label-free detection, high sensitivity, easy operation, and capability of integration, possessing significant potential for application in disease screening and health monitoring. In this perspective, the tremendous efforts and achievements in the development of high-performance FET biosensors in the past decade are summarized, with emphasis on the interface engineering of FET-based electrical platforms for biomolecule identification. First, an overview of engineering strategies for interface modulation and recognition element design is discussed in detail. For a further step, the applications of FET-based electrical devices for in vitro detection and real-time monitoring in biological systems are comprehensively reviewed. Finally, the key opportunities and challenges of FET-based electronic devices in biosensing are discussed. It is anticipated that a comprehensive understanding of interface engineering strategies in FET biosensors will inspire additional techniques for developing highly sensitive, specific, and stable FET biosensors as well as emerging designs for next-generation biosensing electronics.

Redox signaling-driven modulation of microbial biosynthesis and biocatalysis.

Microbial communication can drive coordinated functions through sensing, analyzing and processing signal information, playing critical roles in biomanufacturing and life evolution. However, it is still a great challenge to develop effective methods to construct a microbial communication system with coordinated behaviors. Here, we report an electron transfer triggered redox communication network consisting of three building blocks including signal router, optical verifier and bio-actuator for microbial metabolism regulation and coordination. In the redox communication network, the Fe3+/Fe2+ redox signal can be dynamically and reversibly transduced, channeling electrons directly and specifically into bio-actuator cells through iron oxidation pathway. The redox communication network drives gene expression of electron transfer proteins and simultaneously facilitates the critical reducing power regeneration in the bio-actuator, thus enabling regulation of microbial metabolism. In this way, the redox communication system efficiently promotes the biomanufacturing yield and CO2 fixation rate of bio-actuator. Furthermore, the results demonstrate that this redox communication strategy is applicable both in co-culture and microbial consortia. The proposed electron transfer triggered redox communication strategy in this work could provide an approach for reducing power regeneration and metabolic optimization and could offer insights into improving biomanufacturing efficiency.

Role of ventrolateral part of ventromedial hypothalamus in post-myocardial infarction cardiac dysfunction induced by sympathetic nervous system.

Psychological stress has been recognized as a contributing factor to worsened prognosis in patients with cardiac failure following myocardial infarction (MI). Although the ventrolateral part of the ventromedial hypothalamus (VMHVL) has been implicated in emotional distress, its involvement in post-MI cardiac dysfunction remains largely unexplored. This study was designed to investigate the effect of the VMHVL activation in the MI rat model and its underlying mechanisms. Our findings demonstrate that activation of VMHVL neurons enhances the activity of the cardiac sympathetic nervous system through the paraventricular nucleus (PVN) and superior cervical ganglion (SCG). This activation leads to an elevation in catecholamine levels, which subsequently modulates myosin function and triggers the release of anti-inflammatory factors, to exacerbate the post-MI cardiac prognosis. The denervation of the superior cervical ganglion (SGN) effectively blocked the cardiac sympathetic effects induced by the VMHVL activation, and ameliorated the cardia fibrosis and dysfunction. Therefore, our study identified the role of the "VMHVL-PVN-SCG" sympathetic pathway in the post-MI heart, and proposed SGN as a promising strategy in mitigating cardiac prognosis in stressful rats.

AIEgen-Based Covalent Organic Frameworks for Preventing Malignant Ventricular Arrhythmias Via Local Hyperthermia Therapy.

The engineering of aggregation-induced emission luminogens (AIEgen) based covalent organic frameworks (COFs), TDTA-COF, BTDTA-COF, and BTDBETA-COF are reported, as hyperthermia agents for inhibiting the occurrence of malignant ventricular arrhythmias (VAs). These AIE COFs exhibit dual functionality, as they not only directly modulate the function and neural activity of stellate ganglion (SG) through local hyperthermia therapy (LHT) but also induce the browning of white fat and improve the neuroinflammation peri-SG microenvironment, which is favorable for inhibiting ischemia-induced VAs. In vivo studies have confirmed that BTDBETA-COF-mediated LHT enhances thermogenesis and browning-related gene expression, thereby serving a synergistic role in combating VAs. Transcriptome analysis of peri-SG adipose tissue reveals a substantial downregulation of inflammatory cytokines, highlighting the potency of BTDBETA-COF-mediated LHT in ameliorating the neuroinflammation peri-SG microenvironment and offering myocardial and arrhythmia protection. The work on AIE COF-based hyperthermia agent for VAs inhibition provides a new avenue for mitigating cardiac sympathetic nerve hyperactivity.

Stereotactic arrhythmia radioablation: A novel therapy for cardiac arrhythmia.

Cardiac arrhythmia is a global health problem, and catheter ablation has been one of its main treatments for decades. However, catheter ablation is an invasive method that cannot reach the deep myocardium, and it carries a considerable risk of side effects and recurrence. Therefore, it is necessary to explore a novel approach. Stereotactic body radiotherapy, which has been widely used in the field of radiation oncology, has recently expanded in the treatment of cardiac arrhythmia; when used in this context, it is known as stereotactic arrhythmia radioablation (STAR). As a noninvasive, effective, and well-tolerated treatment, STAR may be a suitable alternative method for patients with cardiac arrhythmia who are resistant or intolerant to catheter ablation. The main particles used to deliver energy in STAR are photons, protons, and carbon ions. Most studies have shown the short-term effectiveness of STAR, but problems such as a high long-term recurrence rate with a cumulative ventricular tachycardia-free survival rate from the published literature of 38.6% and related complications have also emerged. Therefore, in this article, we review the application of stereotactic body radiotherapy in cardiac arrhythmia, analyze its potential problems, and explore methods for improvement.

Wireless Self-Powered Optogenetic System for Long-Term Cardiac Neuromodulation to Improve Post-MI Cardiac Remodeling and Malignant Arrhythmia.

Autonomic imbalance is an important characteristic of patients after myocardial infarction (MI) and adversely contributes to post-MI cardiac remodeling and ventricular arrhythmias (VAs). A previous study proved that optogenetic modulation could precisely inhibit cardiac sympathetic hyperactivity and prevent acute ischemia-induced VAs. Here, a wireless self-powered optogenetic modulation system is introduced, which achieves long-term precise cardiac neuromodulation in ambulatory canines. The wireless self-powered optical system based on a triboelectric nanogenerator is powered by energy harvested from body motion and realized the effective optical illumination that is required for optogenetic neuromodulation (ON). It is further demonstrated that long-term ON significantly mitigates MI-induced sympathetic remodeling and hyperactivity, and improves a variety of clinically relevant outcomes such as improves ventricular dysfunction, reduces infarct size, increases electrophysiological stability, and reduces susceptibility to VAs. These novel insights suggest that wireless ON holds translational potential for the clinical treatment of arrhythmia and other cardiovascular diseases related to sympathetic hyperactivity. Moreover, this innovative self-powered optical system may provide an opportunity to develop implantable/wearable and self-controllable devices for long-term optogenetic therapy.

Ultrasound-mediated piezoelectric nanoparticle modulation of intrinsic cardiac autonomic nervous system for rate control in atrial fibrillation.

Rate control is a cornerstone of atrial fibrillation treatment. Barium titanate nanoparticles (BTNPs) are piezoelectric nanomaterials that can generate local electromagnetic fields under ultrasound activation, stimulating nearby neuronal tissue. This study aimed to modulate the inferior right ganglionated plexus (IRGP) of the heart and reduce the ventricular rate during rapid atrial pacing (RAP)-induced atrial fibrillation using ultrasound-mediated BTNPs. Adult male beagles were randomly divided into a phosphate-buffered saline (PBS) group (n = 6) and a BTNP group (n = 6). PBS or nanoparticles were injected into the IRGP of both groups before RAP. The biological safety of the material was evaluated according to electrophysiology recordings, thermal effects and level of inflammation. Compared to the PBS group, the BaTiO3 piezoelectric nanoparticle group had reduced ventricular rates in the sinus rhythm and atrial fibrillation models after stimulating the IRGP by applying ultrasound. In addition, transient stimulation by BTNPs did not lead to sustained neuronal excitation in the IRGP. The activation of the BTNPs did not induce inflammation or thermal damage effects in the IRGP. Ultrasound-mediated BTNP neuromodulation can significantly reduce the ventricular rate by stimulating the IRGP. Thus, ultrasound-mediated BTNP neuromodulation is a potential therapy for atrial fibrillation rate control.

Effects of pulsed field ablation on autonomic nervous system in paroxysmal atrial fibrillation: A pilot study.

BACKGROUND: Vagal responses and phrenic activation are commonly observed during pulsed field ablation (PFA). However, whether the vagal responses and phrenic activations are nerve damage or a neurological stress response due to electrical stimulation is unclear. OBJECTIVE: The purpose of this study was to evaluate the effect of a PFA system for performing pulmonary vein isolation on the autonomic nervous system. METHODS: Patients with paroxysmal atrial fibrillation (AF) who underwent PFA between August 2021 and November 2021 were included. Nerve injury biomarkers and heart rate variability were obtained preablation and postablation. Patients were scheduled to undergo magnetic resonance imaging and diffusion-weighted imaging to evaluate cerebral microembolus formation postablation. RESULTS: Acute electrical isolation was achieved in 100% of pulmonary veins (n = 72) in the 18 patients. Mean total procedural time was 64.1 ± 18.2 minutes, and mean fluoroscopy time was 12.3 ± 3.5 minutes. Serum nerve injury biomarkers did not show any changes preablation and immediately postablation and 24 hours after ablation (all P >.05). Preablation and 30-day postablation heart rate variability did not differ (all P >.05). Postablation diffusion-weighted imaging revealed no acute cerebral microembolus events. Moreover, there were no other procedure-related complications. The 8-month Kaplan-Meier estimate of freedom from arrhythmia was 83% ± 9%. CONCLUSION: PFA does not induce nerve injury during pulmonary vein isolation for paroxysmal AF.

Bmal1 knockdown in the left stellate ganglion inhibits neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Objectives: The neural activity of the left stellate ganglion (LSG) is closely related to the occurrence of ventricular arrhythmias (VAs). Bmal1 modulates genes associated with neural activity in the central nervous system. However, few studies indicated the role of Bmal1 in the LSG and the subsequent effect on the heart. Therefore, we aimed to investigate the influence of Bmal1 knockdown in the LSG on its neural activity and cardiac electrophysiology and to explore the mechanisms. Materials and methods: We used adeno-associated virus (AAV) to knock down Bmal1 in the LSG. Male beagles were randomized into the Bmal1 knockdown group and the control group. After 4 weeks of injection, the LSG function, neural activity, left ventricular effective refractory period (ERP), and action potential duration (APD) were measured. Electrocardiography for 1 h was recorded for VAs analysis after myocardial ischemia. Nerve growth factor (NGF) and c-fos in the LSG were quantified by immunofluorescence. Transcriptomic analysis was performed to assess the gene expression in the LSG. Results: Bmal1 was sufficiently knocked down by AAV. Compared with the control group, heart rate variability (HRV) in the knockdown group was altered. Bmal1 knockdown inhibited neural activity and function of LSG. It also prolonged ERP as well as APD90. Ischemia-induced VAs were significantly reduced. Nerve growth factor (NGF) and c-fos in the LSG were reduced. Bmal1 knockdown led to the expression changes of genes associated with neural activity in the LSG. Conclusion: Bmal1 knockdown in the LSG suppresses neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Ultrasound-guided injection of botulinum toxin type A blocks cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic myocardial infarction.

BACKGROUND: Strategies to improve various cardiovascular diseases by blocking cardiac sympathetic ganglion have been increasingly available currently. Botulinum toxin type A (BTA), a typical neurotoxin, has been shown to block neural transmission in a safe and long-lasting manner. OBJECTIVE: The aim of the present preclinical study was to assess the efficacy of BTA microinjection to alleviate cardiac remodeling after chronic myocardial infarction (MI) by blocking cardiac sympathetic ganglion in a canine model. METHODS: Beagles were randomly divided into a control group (saline microinjection with sham surgery), an MI group (saline microinjection with MI), and an MI + BTA group (BTA microinjection with MI). Ultrasound-guided percutaneous BTA or saline injection into the left stellate ganglion (LSG) was performed followed by MI induction via left anterior descending artery occlusion (LADO) or sham surgery. After 30 days, electrocardiography, Doppler echocardiography, LSG function, neural activity, and ventricular electrophysiological detection were performed in all experimental dogs. At the end, LSG and ventricular tissues were collected for further detection. RESULTS: BTA treatment significantly inhibited LSG function and neural activity and improved heart rate variability. Additionally, BTA application alleviated ventricular remodeling, ameliorated cardiac function, and prevented ventricular arrhythmias after 30-day chronic LADO-induced MI. CONCLUSION: Ultrasound-guided percutaneous microinjection of BTA can block cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic LADO-induced MI. Ultrasound-guided BTA microinjection has potential for clinical application as a novel cardiac sympathetic ganglion blockade strategy for MI.

Integrated Urinalysis Devices Based on Interface-Engineered Field-Effect Transistor Biosensors Incorporated With Electronic Circuits.

Urinalysis is attractive in non-invasive early diagnosis of bladder cancer compared with clinical gold standard cystoscopy. However, the trace bladder tumor biomarkers in urine and the particularly complex urine environment pose significant challenges for urinalysis. Here, a clinically adoptable urinalysis device that integrates molecular-specificity indium gallium zinc oxide field-effect transistor (IGZO FET) biosensor arrays, a device control panel, and an internet terminal for directly analyzing five bladder-tumor-associated proteins in clinical urine samples, is reported for bladder cancer diagnosis and classification. The IGZO FET biosensors with engineered sensing interfaces provide high sensitivity and selectivity for identification of trace proteins in the complex urine environment. Integrating with a machine-learning algorithm, this device can identify bladder cancer with an accuracy of 95.0% in a cohort of 197 patients and 75 non-bladder cancer individuals, distinguishing cancer stages with an overall accuracy of 90.0% and assessing bladder cancer recurrence after surgical treatment. The non-invasive urinalysis device defines a robust technology for remote healthcare and personalized medicine.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5 and pro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.