Cardiac-specific overexpression of CREM-IbΔC-X via CRISPR/Cas9 in mice presents a new model of atrial cardiomyopathy with spontaneous atrial fibrillation.

Atrial cardiomyopathy (ACM) forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. However, generating stable animal models that accurately replicate the entire progression of atrial lesions, particularly the onset of AF, presents significant challenges. In the present study, we found that the isoform of CRE-binding protein modulator (CREM-IbΔC-X), which is involved in the regulation of cardiac development and atrial rhythm, was highly expressed in atrial biopsies from patients with AF. Building upon this finding, we employed CRISPR/Cas9 technology to create a mouse model with cardiac-specific overexpression of CREM-IbΔC-X (referred to as CS-CREM mice). This animal model effectively illustrated the development of ACM through electrophysiological and structural remodelings over time. Proteomics and Chip-qPCR analysis of atrial samples revealed significant upregulation of cell-matrix adhesion and extracellular matrix structural components, alongside significant downregulation of genes related to atrial functions in the CS-CREM mice. Furthermore, the corresponding responses to anti-arrhythmia drugs, i.e., amiodarone and propafenone, suggested that CS-CREM mice could serve as an ideal in vivo model for drug testing. Our study introduced a novel ACM model with spontaneous AF by cardiac-specifically overexpressing CREM-IbΔC-X in mice, providing valuable insights into the mechanisms and therapeutic targets of ACM.

Magnetic and injectable Fe-doped liquid metals for controlled movement and photothermal/electromagnetic therapy.

As a multifunctional material, gallium-based liquid metal (LM) mixtures with metal particles dispersed in the LM environment display many excellent and intriguing properties. In this study, biomaterials were prepared by mixing Fe particles with LM for easily manageable photothermal or electromagnetic therapy and evaluated. Clinically, the fabricated 5%Fe/LM sample was injectable and radiopaque, which allowed its smooth delivery through a syringe to the target tissues, where it could help achieve clear imaging under CT. Meanwhile, because of the loading of Fe particles, the 5%Fe/LM possessed a magnetic property, implying a high manipulation capability. According to the experiments, the capsule containing 5%Fe/LM when placed in an isolated pig large intestine could move as desired to the designated position through an external magnet. Further, the biosafety and low toxicity of the 5%Fe/LM were confirmed by cytotoxicity tests in vitro, and the temperature changes at the interface between the 5%Fe/LM and intestinal tissue after near-infrared (NIR) laser irradiation were determined through theoretical modeling and numerical simulation data analysis. Due to the excellent photothermal and magnetothermal effects of LM, the temperature of the 5%Fe/LM injected into the rabbit abdominal cavity could significantly increase under NIR laser or alternating magnetic field (AMF) administration. As a novel functional biomaterial, the 5%Fe/LM exhibited promising potential for designated position movement and photothermal or magnetothermal therapy in the near future.

Liquid Metal Memory.

Storage systems are vital components of electronic devices, while significant challenges persist in achieving flexible memory due to the limitations of existing storage methodologies. Inspired by the polarization and depolarization mechanisms in the human brain, here a novel class of storage principles is proposed and achieve a fully flexible memory through introducing the oxidation and deoxidation behaviors of liquid metals. Specifically, reversible electrochemical oxidation is utilized to modulate the overall conductivity of the target liquid metals, creating a substantial 11-order resistance difference for binary data storage. To obtain the best storage performance, systematic optimizations of multiple parameters are conducted. Conceptual experiments demonstrate the memory's stability under extreme deformations (100% stretching, 180° bending, 360° twisting). Further tests reveal that the memory performs better when its unit size gets smaller, warranting superior integrability. Finally, a complete storage system achieves remarkable performance metrics, including rapid storage speed (>33 Hz), long data retention capacity (>43200 s), and stable repeatable operation (>3500 cycles). This groundbreaking method not only overcomes the inherent rigidity limitations of existing electronic storage units but also opens new possibilities for innovating neuromorphic devices, offering fundamental and practical avenues for future applications in soft robotics, wearable electronics, and bio-inspired artificial intelligence systems.

Increased A1 astrocyte activation-driven hippocampal neural network abnormality mediates delirium-like behavior in aged mice undergoing cardiac surgery.

Delirium is the most common neurological complication after cardiac surgery with adverse impacts on surgical outcomes. Advanced age is an independent risk factor for delirium occurrence but its underlying mechanisms are not fully understood. Although increased A1 astrocytes and abnormal hippocampal networks are involved in neurodegenerative diseases, whether A1 astrocytes and hippocampal network changes are involved in the delirium-like behavior of aged mice remains unknown. In the present study, a mice model of myocardial ischemia-reperfusion mimicking cardiac surgery and various assessments were used to investigate the different susceptibility of the occurrence of delirium-like behavior between young and aged mice and the underlying mechanisms. The results showed that surgery significantly increased hippocampal A1 astrocyte activation in aged compared to young mice. The high neuroinflammatory state induced by surgery resulted in glutamate accumulation in the extrasynaptic space, which subsequently decreased the excitability of pyramidal neurons and increased the PV interneurons inhibition through enhancing N-methyl-D-aspartate receptors' tonic currents in the hippocampus. These further induced the abnormal activities of the hippocampal neural networks and consequently contributed to delirium-like behavior in aged mice. Notably, the intraperitoneal administration of exendin-4, a glucagon-like peptide-1 receptor agonist, downregulated A1 astrocyte activation and alleviated delirium-like behavior in aged mice, while IL-1α, TNF-α, and C1q in combination administered intracerebroventricularly upregulated A1 astrocyte activation and induced delirium-like behavior in young mice. Therefore, our study suggested that cardiac surgery increased A1 astrocyte activation which subsequently impaired the hippocampal neural networks and triggered delirium development.

Safety of open limited surgery for septuagenarian and octogenarian acute type A aortic dissection patients: a retrospective cohort study.

Background: Surgical strategies in older adult patients with acute type A aortic dissection (aTAAD) are crucial. We investigated the safety and efficiency of open limited surgery for septuagenarian and octogenarian patients with aTAAD. Methods: Between 2011 and 2019, 1,092 patients diagnosed with aTAAD underwent open surgery in Nanjing Drum Tower Hospital. Patients were divided into two groups based on age: <70 years (n=956) and ≥70 years (n=136). Preoperative baseline characteristics, operative data, and postoperative outcomes were compared between the two groups. To investigate the safety and efficiency of the surgical approach for those aged ≥70 years, we separated these patients into two groups: (I) those who underwent root-sparing surgery and less-invasive arch surgery (Limited group; n=86); and (II) all others (Extensive group; n=50). Results: Mortality was significantly higher in those aged ≥70 years than in those <70 years (20.6% vs. 13.2%; P=0.000), with age being a strong risk factor for postoperative mortality [odds ratio (OR) 1.619; 95% confidence interval (CI): 1.015-2.582; P=0.043]. Patients aged ≥70 years tended to receive less invasive surgery, and the rates of root replacement and arch replacement were lower. Patients in the limited surgery group had a higher rate of pericardial tamponade, and the durations of surgery, hypothermic circulation arrest, cardiopulmonary bypass, and aortic clamp were all significantly shorter than in the extensive group. Mortality and postoperative complications were also lower in the limited surgery group. Conclusions: Although older age was a risk factor for open surgery for aTAAD, limited surgical techniques could lower the mortality and morbidity regardless of the need for extensive surgery.

A Photothermally Enhanced Vancomycin-Coated Liquid Metal Antimicrobial Agent with Targeting Capability.

The targeted antimicrobial efficacy of Vancomycin decreases significantly over time due to bacterial resistance, whereas Ga-based liquid metals, which are less prone to inducing bacterial resistance, face challenges in achieving targeted antimicrobial effects. To tackle these issues, a highly efficient antimicrobial agent with targeting properties has been developed by combining Ga-based liquid metals and Vancomycin. Moreover, the performance of this antimicrobial agent can be greatly enhanced through the use of near-infrared light. Microscopic observations reveal that Vancomycin can be effectively encapsulated on the surface of liquid metal, facilitated by the presence of the oxide layer. The resulting core-shell structured antimicrobial agent demonstrates notable targeted antimicrobial effects against S. aureus. Antibacterial tests indicate that Vancomycin effectively improves the antibacterial properties of pure liquid metal. Additionally, this study unveils the excellent photothermal conversion capabilities of liquid metal, enabling the antimicrobial agent exposed to 808nm near-infrared light to exhibit significantly strengthened bactericidal performance. In this scenario, the antimicrobial agent can achieve nearly 100% effectiveness. This work enriches the investigation of integrating Ga-based antimicrobial agents with traditional antibiotics, showcasing promising antibacterial effects and establishing the groundwork for subsequent clinical applications.

In Situ Fabricated Liquid Metal Capacitors for Plant Sensing.

Capacitive sensors are essential to promoting modernization and intelligence in agriculture. With the continuous advancement of this sensor technology, the demand for materials with high conductivity and flexibility is rapidly increasing. Herein, we introduce liquid metal as a solution for the in-site fabrication of high-performance capacitive sensors for plant sensing. As a comparison, three pathways have been proposed for the preparation of flexible capacitors inside plants, as well as on their surfaces. Specifically, concealed capacitors can be constructed by directly injecting liquid metal into the plant cavity. Printable capacitors are prepared via printing Cu-doped liquid metal with better adhesion on plant surfaces. A composite liquid metal-based capacitive sensor is achieved by printing liquid metal on the plant surface and injecting it into the interior of the plant. While each method has limitations, the composite liquid metal-based capacitive sensor provides an optimal trade-off between signal capture capability and operability. As a result, this composite capacitor is chosen as a sensor for monitoring water changes within plants and demonstrates the desired sensing performance, making it a promising technology for monitoring plant physiology.

Absence of near-ambient superconductivity in LuH2±xNy.

A recent study demonstrated near-ambient superconductivity in nitrogen-doped lutetium hydride1. This stimulated a worldwide interest in exploring room-temperature superconductivity at low pressures. Here, by using a high-pressure and high-temperature synthesis technique, we have obtained nitrogen-doped lutetium hydride (LuH2±xNy), which has a dark-blue colour and a structure with the space group [Formula: see text] as evidenced by X-ray diffraction. This structure is the same as that reported in ref. 1, with a slight difference in lattice constant. Raman spectroscopy of our samples also showed patterns similar to those observed in ref. 1. Energy-dispersive X-ray spectroscopy confirmed the presence of nitrogen in the samples. We observed a metallic behaviour from 350 K to 2 K at ambient pressure. On applying pressures from 2.1 GPa to 41 GPa, we observed a gradual colour change from dark blue to violet to pink-red. By measuring the resistance at pressures ranging from 0.4 GPa to 40.1 GPa, we observed a progressively improved metallic behaviour; however, superconductivity was not observed above 2 K. Temperature dependence of magnetization at high pressure shows a very weak positive signal between 100 K and 320 K, and the magnetization increases with an increase in magnetic field at 100 K. All of these are not expected for superconductivity above 100 K. Thus, we conclude the absence of near-ambient superconductivity in this nitrogen-doped lutetium hydride at pressures below 40.1 GPa.

Analysis of risk factors for postoperative mortality in acute type A aortic dissection patients under different critical levels.

We built up a risk stratification model to divide acute type A aortic dissection (aTAAD) patients into low- and high-risk groups, further, to evaluate the risk factors for postoperative mortality. A total of 1364 patients from 2010 to 2020 in our center were retrospectively analyzed. More than twenty clinical variables were related with postoperative mortality. The postoperative mortality of the high-risk patients was doubled than the low-risk ones (21.8% vs 10.1%). The increased operation time, combined coronary artery bypass graft, cerebral complications, re-intubation, continuous renal replacement therapy and surgical infection were risk factors of postoperative mortality in low-risk patients. In addition, postoperative lower limbs or visceral malperfusion were risk factors, axillary artery cannulation and moderate hypothermia were protective factors in high-risk patients. A scoring system for quick decision-making is needed to select appropriate surgical strategy in aTAAD patients. For low-risk patients, different surgical treatments can be performed with similar clinical prognosis. Limited arch treatment and appropriate cannulation approach are crucial in high-risk aTAAD patients.

Short and mid-term effects of modified release technique in rheumatic mitral valve repair.

OBJECTIVE: Repair or replacement remains debatable in rheumatic heart disease. To regain optimal mean transvalvular pressure gradients and end-diastolic peak flow velocity, the modified release technique combined peeling in the anterior leaflet and separated the shortened chordal. In the end, the short and mid-term outcomes of the modified release technique were evaluated. METHODS: We retrospectively analyzed a series of 128 patients with rheumatic mitral stenosis, from January 2018 to July 2021 in our center. All patients undergoing mitral valve repair were using the modified release technique. The effect of mitral valve repair was evaluated by intraoperative transesophageal echocardiography and postoperative transthoracic echocardiography. RESULTS: All the 128 patients successfully repaired the mitral valve. The intraoperative transesophageal echocardiography showed trivial or mild regurgitation. The aortic valve was repaired without obvious regurgitation in 12 cases, 5 cases received an aortic valve replacement, 89 cases underwent tricuspid annuloplasty. There were no blood transfusions in most patients, no deaths nor complications during peri-operation, also, no deaths and adverse events were observed during the follow-up period from 3 to 42 months. During the follow-up, 122 cases had no mitral valve regurgitation and 2 cases of moderate regurgitation, 4 cases of mild to moderate regurgitation. The mean peak flow velocity was 1.2 ± 0.3 m / s, no new-onset stenosis occurred. CONCLUSION: Modified release technique is safe and feasible. Its durability is acceptable in the short and mid-term, with no new-onset stenosis during the follow-up.

Binary Colloidal Crystals Promote Cardiac Differentiation of Human Pluripotent Stem Cells via Nuclear Accumulation of SETDB1.

Biophysical cues can facilitate the cardiac differentiation of human pluripotent stem cells (hPSCs), yet the mechanism is far from established. One of the binary colloidal crystals, composed of 5 µm Si and 400 nm poly(methyl methacrylate) particles named 5PM, has been applied as a substrate for hPSCs cultivation and cardiac differentiation. In this study, cell nucleus, cytoskeleton, and epigenetic states of human induced pluripotent stem cells on the 5PM were analyzed using atomic force microscopy, molecular biology assays, and the assay for transposase-accessible chromatin sequencing (ATAC-seq). Cells were more spherical with stiffer cell nuclei on the 5PM compared to the flat control. ATAC-seq revealed that chromatin accessibility decreased on the 5PM, caused by the increased entry of histone lysine methyltransferase SETDB1 into the cell nuclei and the amplified level of histone H3K9me3 modification. Reducing cytoskeleton tension using a ROCK inhibitor attenuated the nuclear accumulation of SETDB1 on the 5PM, indicating that the effect is cytoskeleton-dependent. In addition, the knockdown of SETDB1 reversed the promotive effects of the 5PM on cardiac differentiation, demonstrating that biophysical cue-induced cytoskeletal tension, cell nucleus deformation, and then SETDB1 accumulation are critical outside-in signal transformations in cardiac differentiation. Human embryonic stem cells showed similar results, indicating that the biophysical impact of the 5PM surfaces on cardiac differentiation could be universal. These findings contribute to our understanding of material-assistant hPSC differentiation, which benefits materiobiology and stem cell bioengineering.

Flexible Skin Patch Enabled Tumor Hybrid Thermophysical Therapy and Adaptive Antitumor Immune Response.

Innovations on materials and technologies have greatly promoted the rapid development of wearable electronics from disease diagnosis to therapeutics. For superficial skin tumors, skin-attachable patches possess the advantages of minimally invasive property, alleviative side effects, and high efficiency. The development of noninvasive techniques and devices is still in urgent demands. Here, a flexible skin patch fabricated through a facile preparation method is reported for noninvasive hybrid thermophysical therapy and adaptative immune function enhancement. The liquid metal enabled skin patch is demonstrated with high conductivity, certain stability, biocompatibility, and an enhanced adhesive merit on skin surfaces for cryoablation therapy and magnetic hyperthermia therapy. The skin patch exhibits remarkably conformable heating and cooling performance toward the treatment of 4T1 breast tumors. The magnetic resonance images also indicate the significant tumor ablation effect. Interestingly, a relatively stable proportion of both CD8+ T and CD4+ T cells in the peripheral blood is identified after tumor therapy in comparison with the decreased trend in the untreated group, representing an efficient antitumor immune response induced by the skin patch. The developed skin patch would provide a promising noninvasive approach for tumor therapies by direct tumor destruction and maintenance of the antitumor immune response.

Sex- and exposure age-dependent effects of adolescent stress on ventral tegmental area dopamine system and its afferent regulators.

Adolescent stress is a risk factor for schizophrenia. Emerging evidence suggests that age-dependent sensitive windows for childhood trauma are associated more strongly with adult psychosis, but the neurobiological basis and potential sex differences are unknown.Using in vivo electrophysiology and immunohistology in rats, we systematically compared the effects of two age-defined adolescent stress paradigms, prepubertal (postnatal day [PD] 21-30; PreP-S) and postpubertal (PD41-50; PostP-S) foot-shock and restraint combined stress, on ventral tegmental area (VTA) dopaminergic activity, pyramidal neuron activity in the ventral hippocampus (vHipp) and the basolateral amygdala (BLA), corticoamygdalar functional inhibitory control, and vHipp and BLA parvalbumin interneuron (PVI) impairments. These endpoints were selected based on their well-documented roles in the pathophysiology of psychosis.Overall, we found distinct sex- and exposure age-dependent stress vulnerability. Specifically, while males were selectively vulnerable to PreP-S-induced adult VTA dopamine neuron and vHipp hyperactivities, females were selectively vulnerable to PostP-S. These male selective PreP-S effects were correlated with stress-induced aberrant persistent BLA hyperactivity, dysfunctional prefrontal inhibitory control of BLA neurons, and vHipp/BLA PVI impairments. In contrast, female PostP-S only produced vHipp PVI impairments in adults, with the BLA structure and functions largely unaffected.Our results indicated distinct adolescent-sensitive periods during which stress can sex-dependently confer maximal risks to corticolimbic systems to drive dopamine hyperactivity, which provide critical insights into the neurobiological basis for sex-biased stress-related psychopathologies emphasizing but not limited to schizophrenia. Furthermore, our work also provides a framework for future translational research on age-sensitive targeted interventions.

Neonatal ketone body elevation regulates postnatal heart development by promoting cardiomyocyte mitochondrial maturation and metabolic reprogramming.

Neonatal heart undergoes metabolic conversion and cell cycle arrest preparing for the increased workload during adulthood. Herein, we report that neonatal ketone body elevation is a critical regulatory factor for postnatal heart development. Through multiomics screening, we found that the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, was transiently induced by colostrum in the neonatal heart. Hmgcs2 knockout caused mitochondrial maturation defects. Meanwhile, postnatal heart development was compromised and cardiomyocytes reacquired proliferation capacity in Hmgcs2 knockout mice. Consequently, over 40% of newborn Hmgcs2 knockout mice died before weaning. The heart function of surviving Hmgcs2 knockout mice was also impaired, which could be rescued by ketone body supplementation during the suckling stage. Mechanistically, ketone body deficiency inhibited ß-hydroxybutyrylation but enhanced acetylation of mitochondrial proteins, which might be responsible for the inhibition of the enzyme activity in mitochondria. These observations suggest that ketone body is critical for postnatal heart development through regulating mitochondrial maturation and metabolic reprogramming.

"Collar-like" neocommissure in mitral valve repair for extensive commissural prolapse.

Objectives: Mitral valve repair for extensive commissural prolapse is complex; several methods have been reported with variable results. To restore the leaflet area, we introduced an innovative and effective method rather than a simple folding technique through reconstructing a neocommissure with a "collar-like" plasty technique. Methods: From 2016 to 2021, 62 patients with mitral valve extensive commissural prolapse that received the "collar-like" plasty technique were included. Results: The mean age was 51.7 ± 13.8 years, and 38 (61%) were female. Postplasty transesophageal echocardiography showed the mean transvalvular pressure gradients were 3.8 ± 1.2 mm Hg, end diastolic peak flow velocity was 1.1 ± 0.3 m/s, and coaptation height was 7.9 ± 1.1 mm. During the follow-up period of 3 to 6 months, no deaths or cardiovascular-/valvular plasty-related adverse events occurred. All patients regained their heart function and returned to normal physical activities. Conclusions: The "collar-like" plasty technique can be safely performed for patients with extensive commissural prolapse. Echocardiography revealed that the technique can restore the leaflet area of low transvalvular pressure and flow velocity.

Using animal models for the studies of schizophrenia and depression: The value of translational models for treatment and prevention.

Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials.

Design, synthesis, and anticancer activity of three novel palbociclib derivatives.

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.

Phase-Transitional Bismuth-Based Metals enable Rapid Embolotherapy, Hyperthermia, and Biomedical Imaging.

Embolization has been an important minimally invasive therapy for occlusion of malfunctioned vasculature and tumor treatment via target delivering embolic agents. The limitation of conventional embolic agents, such as fabrication process, precipitation time, invisibility, and lack of integrated functions often leads to insufficient embolization efficacy. To overcome these drawbacks, a multifunctional bismuth (Bi)-based liquid embolic agent for simultaneous realization of embolotherapy, thermotherapy, as well as high-contrast biomedical imaging is proposed. Benefitting from the suitable melting point, flexible nature, metallic merit, and easygoing operation via injection, the versatile embolic agent can achieve rapid liquid-solid phase transition, magnetic hyperthermia, and multimodal imaging capability. The Bi-based materials are demonstrated with excellent arteriovenous embolization efficiency and favorable biocompatibility according to in vivo investigations. Introduction of the liquid embolic agent to tumor arteries achieves evident tumor regression and rather clear imaging under computed tomography (CT), magnetic resonance imaging (MRI), and thermographs for consistently tracking the implants over the biological body. Further, the combined therapy coupled with thermotherapy exhibits improved therapeutic efficiency with formation of necrosis and total tumor eradiation at day 15 after the treatment. The present innovative embolic agent and the surgical principle provide a promising modality for embolization and potential theranostic platform of tumors.

Unsupervised machine learning reveals epicardial adipose tissue subtypes with distinct atrial fibrosis profiles in patients with persistent atrial fibrillation: A prospective 2-center cohort study.

BACKGROUND: Epicardial adipose tissue (EAT) accumulation is associated with the progression of atrial fibrillation. However, the histological features of EATs are poorly defined and their correlation with atrial fibrosis is unclear. OBJECTIVE: The purpose of this study was to identify and characterize EAT subgroups in the persistent atrial fibrillation (PeAF) cohorts. METHODS: EATs and the corresponding left atrial appendage samples were obtained from patients with PeAF via surgical intervention. Adipocyte markers, that is, Uncoupling Protein 1, Transcription Factor 21, and CD137, were examined. On the basis of expression of adipocyte markers, patients with PeAF were categorized into subgroups by using unsupervised clustering analysis. Clinical characteristics, histological analyses, and outcomes were subsequently compared across the clusters. External validation was performed in a validation cohort. RESULTS: The ranking of feature importance revealed that the 3 adipocyte markers were the most relevant factors for atrial fibrosis compared with other clinical indicators. On the k-medoids analysis, patients with PeAF could be categorized into 3 clusters in the discovery cohort. The histological studies revealed that patients in cluster 1 exhibited statistically larger size of adipocytes in EATs and severe atrial fibrosis in left atrial appendages. Findings were replicated in the validation cohort, where severe atrial fibrosis was noted in cluster 1. Moreover, in the validation cohort, there was a high degree of overlap between the supervised classification results and the unsupervised cluster results from the k-medoids method. CONCLUSION: Machine learning-based cluster analysis could identify subtypes of patients with PeAF having distinct atrial fibrosis profiles. Additionally, EAT whitening (increased proportion of white adipocytes) may be involved in the process of atrial fibrosis.

Epicardial injection of allogeneic human-induced-pluripotent stem cell-derived cardiomyocytes in patients with advanced heart failure: protocol for a phase I/IIa dose-escalation clinical trial.

INTRODUCTION: Heart failure (HF) is a growing global public health burden. However, due to the very limited regenerative capacity of mature cardiomyocytes in the adult mammalian heart, conventional treatments can only improve the symptoms of HF but fail to restore cardiac function. Heart transplantation is limited by a severe shortage of donors. Cell-based transplantation for the treatment of HF has become a promising strategy. Human-induced-pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been tested in animal models to assess safety and efficacy. This study aims at evaluating the safety and efficacy of epicardial injection of hiPSC-CMs in patients with advanced HF during coronary artery bypass grafting (CABG) surgery. METHODS: This study is a dose-escalation, placebo-controlled, single-centre phase I/IIa clinical trial. Dose escalation will be guided by a modified 3+3 design for three doses (1×108, 2×108 and 4×108 cells, sequentially). Patients with advanced heart failure will be enrolled and randomly allocated to receive epicardial injection of hiPSC-CMs during CABG surgery or CABG surgery alone, followed by a 12-month follow-up investigation. The primary endpoint is to assess the safety of hiPSC-CMs transplantation, including haemodynamic compromised sustained ventricular arrhythmias and newly formed tumours during 6 months postoperatively. The secondary endpoint is to evaluate the efficacy of epicardial injection of hiPSC-CMs and CABG surgery combination by comparison with CABG surgery alone. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Ethical Committee of Nanjing Drum Tower Hospital (No. SC202000102) and approved by National Health Commission of the PRC (MR-32-21-014649). Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. TRIAL REGISTRATION NUMBER: NCT03763136.