Centriole signaling restricts hepatocyte ploidy to maintain liver integrity.

Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome-P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease.

Modulation of tooth regeneration through opposing responses to Wnt and BMP signals in teleosts.

Most vertebrate species undergo tooth replacement throughout adult life. This process is marked by the shedding of existing teeth and the regeneration of tooth organs. However, little is known about the genetic circuitry regulating tooth replacement. Here, we tested whether fish orthologs of genes known to regulate mammalian hair regeneration have effects on tooth replacement. Using two fish species that demonstrate distinct modes of tooth regeneration, threespine stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio), we found that transgenic overexpression of four different genes changed tooth replacement rates in the direction predicted by a hair regeneration model: Wnt10a and Grem2a increased tooth replacement rate, whereas Bmp6 and Dkk2 strongly inhibited tooth formation. Thus, similar to known roles in hair regeneration, Wnt and BMP signals promote and inhibit regeneration, respectively. Regulation of total tooth number was separable from regulation of replacement rates. RNA sequencing of stickleback dental tissue showed that Bmp6 overexpression resulted in an upregulation of Wnt inhibitors. Together, these data support a model in which different epithelial organs, such as teeth and hair, share genetic circuitry driving organ regeneration.

Structure, function and formation of the amniote skin pattern.

From feather and hair dotted arrays to pigmented stripes and spots, the spatial distribution of skin appendages and colouration often forms visible ornaments crucial for fitness in the coat of birds and mammals. These geometrical motifs are extremely diverse in nature. Yet, phenotypic surveys evidenced common themes in variation: the orientation, appendage-specificity or pigmentation of a given region may be conserved across groups or species. Here, we review naturalist observations of natural variation in the anatomy and ecological function of the skin pattern in amniotes. We then describe several decades of genetics, mathematical modelling and experimental embryology work aiming at understanding the molecular and morphogenetic mechanisms responsible for pattern formation. We discuss how these studies provided evidence that the morphological trends and differences representative of the phenotypic landscape of skin patterns in wild amniote species is rooted in the mechanisms controlling the production of distinct compartments in the embryonic skin.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Artificial intelligence in detecting left atrial appendage thrombus by transthoracic echocardiography and clinical features: the Left Atrial Thrombus on Transoesophageal Echocardiography (LATTEE) registry.

AIMS: Transoesophageal echocardiography (TOE) is often performed before catheter ablation or cardioversion to rule out the presence of left atrial appendage thrombus (LAT) in patients on chronic oral anticoagulation (OAC), despite associated discomfort. A machine learning model [LAT-artificial intelligence (AI)] was developed to predict the presence of LAT based on clinical and transthoracic echocardiography (TTE) features. METHODS AND RESULTS: Data from a 13-site prospective registry of patients who underwent TOE before cardioversion or catheter ablation were used. LAT-AI was trained to predict LAT using data from 12 sites (n = 2827) and tested externally in patients on chronic OAC from two sites (n = 1284). Areas under the receiver operating characteristic curve (AUC) of LAT-AI were compared with that of left ventricular ejection fraction (LVEF) and CHA2DS2-VASc score. A decision threshold allowing for a 99% negative predictive value was defined in the development cohort. A protocol where TOE in patients on chronic OAC is performed depending on the LAT-AI score was validated in the external cohort. In the external testing cohort, LAT was found in 5.5% of patients. LAT-AI achieved an AUC of 0.85 [95% confidence interval (CI): 0.82-0.89], outperforming LVEF (0.81, 95% CI 0.76-0.86, P < .0001) and CHA2DS2-VASc score (0.69, 95% CI: 0.63-0.7, P < .0001) in the entire external cohort. Based on the proposed protocol, 40% of patients on chronic OAC from the external cohort would safely avoid TOE. CONCLUSION: LAT-AI allows accurate prediction of LAT. A LAT-AI-based protocol could be used to guide the decision to perform TOE despite chronic OAC.

Residual leaks following percutaneous left atrial appendage occlusion and outcomes: a meta-analysis.

BACKGROUND AND AIMS: Residual leaks are not infrequent after left atrial appendage occlusion. However, there is still uncertainty regarding their prognostic implications. The aim of this study is to evaluate the impact of residual leaks after left atrial appendage occlusion. METHODS: A literature search was conducted until 19 February 2023. Residual leaks comprised peri-device leaks (PDLs) on transoesophageal echocardiography (TEE) or computed tomography (CT), as well as left atrial appendage patency on CT. Random-effects meta-analyses were performed to assess the clinical impact of residual leaks. RESULTS: Overall 48 eligible studies (44 non-randomized/observational and 4 randomized studies) including 61 666 patients with atrial fibrillation who underwent left atrial appendage occlusion were analysed. Peri-device leak by TEE was present in 26.1% of patients. Computed tomography-based left atrial appendage patency and PDL were present in 54.9% and 57.3% of patients, respectively. Transoesophageal echocardiography-based PDL (i.e. any reported PDL regardless of its size) was significantly associated with a higher risk of thromboembolism [pooled odds ratio (pOR) 2.04, 95% confidence interval (CI): 1.52-2.74], all-cause mortality (pOR 1.16, 95% CI: 1.08-1.24), and major bleeding (pOR 1.12, 95% CI: 1.03-1.22), compared with no reported PDL. A positive graded association between PDL size and risk of thromboembolism was noted across TEE cut-offs. For any PDL of >0, >1, >3, and >5 mm, the pORs for thromboembolism were 1.82 (95% CI: 1.35-2.47), 2.13 (95% CI: 1.04-4.35), 4.14 (95% CI: 2.07-8.27), and 4.44 (95% CI: 2.09-9.43), respectively, compared with either no PDL or PDL smaller than each cut-off. Neither left atrial appendage patency, nor PDL by CT was associated with thromboembolism (pOR 1.45 and 1.04, 95% CI: 0.84-2.50 and 0.52-2.07, respectively). CONCLUSIONS: Peri-device leak detected by TEE was associated with adverse events, primarily thromboembolism. Residual leaks detected by CT were more frequent but lacked prognostic significance.

Left atrial appendage closure for stroke prevention in atrial fibrillation: current status and perspectives.

Atrial fibrillation (AF) is associated with an increased risk of stroke and systemic embolism, and the left atrial appendage (LAA) has been identified as a principal source of thromboembolism in these patients. While oral anticoagulation is the current standard of care, LAA closure (LAAC) emerges as an alternative or complementary treatment approach to reduce the risk of stroke or systemic embolism in patients with AF. Moderate-sized randomized clinical studies have provided data for the efficacy and safety of catheter-based LAAC, largely compared with vitamin K antagonists. LAA device iterations, advances in pre- and peri-procedural imaging, and implantation techniques continue to increase the efficacy and safety of LAAC. More data about efficacy and safety of LAAC have been collected, and several randomized clinical trials are currently underway to compare LAAC with best medical care (including non-vitamin K antagonist oral anticoagulants) in different clinical settings. Surgical LAAC in patients with AF undergoing cardiac surgery reduced the risk of stroke on background of anticoagulation therapy in the LAAOS III study. In this review, we describe the rapidly evolving field of LAAC and discuss recent clinical data, ongoing studies, open questions, and current limitations of LAAC.

Protein signaling and morphological development of the tail fluke in the embryonic beluga whale (Delphinapterus leucas).

BACKGROUND: During the land-to-sea transition of cetaceans (whales, dolphins, and porpoises), the hindlimbs were lost and replaced by an elaborate tail fluke that evolved 32 Ma. All modern cetaceans utilize flukes for lift-based propulsion, and nothing is known of this organ's molecular origins during embryonic development. This study utilizes immunohistochemistry to identify the spatiotemporal location of protein signals known to drive appendage outgrowth in other vertebrates (e.g., Sonic Hedgehog [SHH], GREMLIN [GREM], wingless-type family member 7a [WNT], and fibroblast growth factors [FGFs]) and to test the hypothesis that signals associated with outgrowth and patterning of the tail fluke are similar to a tetrapod limb. Specifically, this study utilizes an embryo of a beluga whale (Delphinapterus leucas) as a case study. RESULTS: Results showed epidermal signals of WNT and FGFs, and mesenchymal/epidermal signals of SHH and GREM. These patterns are most consistent with vertebrate limb development. Overall, these data are most consistent with the hypothesis that outgrowth of tail flukes in cetaceans employs a signaling pattern that suggests genes essential for limb outgrowth and patterning shape this evolutionarily novel appendage. CONCLUSIONS: While these data add insights into the molecular signals potentially driving the evolution and development of tail flukes in cetaceans, further exploration of the molecular drivers of fluke development is required.

Effects of life history strategies and habitats on limb regeneration in plethodontid salamanders.

BACKGROUND: Salamanders are the only tetrapods that exhibit the ability to fully regenerate limbs. The axolotl, a neotenic salamander, has become the model organism for regeneration research. Great advances have been made providing a detailed understanding of the morphological and molecular processes involved in limb regeneration. However, it remains largely unknown how limb regeneration varies across salamanders and how factors like variable life histories, ecologies, and limb functions have influenced and shaped regenerative capacities throughout evolution. RESULTS: This study focuses on six species of plethodontid salamanders representing distinct life histories and habitats. Specimens were examined for regeneration ability after bite injuries as well as after controlled amputations. Morphological investigations revealed great regenerative abilities in all investigated species and frequent anatomical limb anomalies. Correlations were observed with respect to speed of regeneration and habitat. CONCLUSIONS: Investigating regeneration in non-model salamander taxa is essential for disentangling shared features of the regeneration process versus those that may be more taxon-specific. Gaining insights into variable aspects of regeneration under natural conditions and after conspecific biting rather than controlled amputations adds important new datapoints for understanding the evolutionary framework of regeneration and provides a broader context for interpreting findings made in the model organism axolotl.

Differential requirements for the Eps15 homology domain proteins EHD4 and EHD2 in the regulation of mammalian ciliogenesis.

The endocytic protein EHD1 controls primary ciliogenesis by facilitating fusion of the ciliary vesicle and by removal of CP110 from the mother centriole. EHD3, the closest EHD1 paralog, has a similar regulatory role, but initial evidence suggested that the other two more distal paralogs, EHD2 and EHD4 may be dispensable for ciliogenesis. Herein, we define a novel role for EHD4, but not EHD2, in regulating primary ciliogenesis. To better understand the mechanisms and differential functions of the EHD proteins in ciliogenesis, we first demonstrated a requirement for EHD1 ATP-binding to promote ciliogenesis. We then identified two sequence motifs that are entirely conserved between EH domains of EHD1, EHD3 and EHD4, but display key amino acid differences within the EHD2 EH domain. Substitution of either P446 or E470 in EHD1 with the aligning S451 or W475 residues from EHD2 was sufficient to prevent rescue of ciliogenesis in EHD1-depleted cells upon reintroduction of EHD1. Overall, our data enhance the current understanding of the EHD paralogs in ciliogenesis, demonstrate a need for ATP-binding and identify conserved sequences in the EH domains of EHD1, EHD3 and EHD4 that regulate EHD1 binding to proteins and its ability to rescue ciliogenesis in EHD1-depleted cells.

Oral Anticoagulation Use and Left Atrial Appendage Occlusion in LAAOS III.

BACKGROUND: LAAOS III (Left Atrial Appendage Occlusion Study III) showed that left atrial appendage (LAA) occlusion reduces the risk of ischemic stroke or systemic embolism in patients with atrial fibrillation undergoing cardiac surgery. This article examines the effect of LAA occlusion on stroke reduction according to variation in the use of oral anticoagulant (OAC) therapy. METHODS: Information regarding OAC use was collected at every follow-up visit. Adjusted proportional hazards modeling, including using landmarks of hospital discharge, 1 and 2 years after randomization, evaluated the effect of LAA occlusion on the risk of ischemic stroke or systemic embolism, according to OAC use. Adjusted proportional hazard modeling, with OAC use as a time-dependent covariate, was also performed to assess the effect of LAA occlusion, according to OAC use throughout the study. RESULTS: At hospital discharge, 3027 patients (63.5%) were receiving a vitamin K antagonist, and 879 (18.5%) were receiving a non-vitamin K antagonist oral anticoagulant (direct OAC), with no difference in OAC use between treatment arms. There were 2887 (60.5%) patients who received OACs at all follow-up visits, 1401 (29.4%) who received OAC at some visits, and 472 (9.9%) who never received OACs. The effect of LAA occlusion on the risk of ischemic stroke or systemic embolism was consistent after discharge across all 3 groups: hazard ratios of 0.70 (95% CI, 0.51-0.96), 0.63 (95% CI, 0.43-0.94), and 0.76 (95% CI, 0.32-1.79), respectively. An adjusted proportional hazards model with OAC use as a time-dependent covariate showed that the reduction in stroke or systemic embolism with LAA occlusion was similar whether patients were receiving OACs or not. CONCLUSIONS: The benefit of LAA occlusion was consistent whether patients were receiving OACs or not. LAA occlusion provides thromboembolism reduction in patients independent of OAC use.

Atrial Fibrillation Detection and Load: Knowledge Gaps Related to Stroke Prevention.

Atrial fibrillation is a major cause of ischemic stroke. Technological advances now support prolonged cardiac rhythm monitoring using either surface electrodes or insertable cardiac monitors. Four major randomized controlled trials show that prolonged cardiac monitoring detects subclinical paroxysmal atrial fibrillation in 9% to 16% of patients with ischemic stroke, including in patients with potential alternative causes such as large artery disease or small vessel occlusion; however, the optimal monitoring strategy, including the target patient population and the monitoring device (whether to use an event monitor, insertable cardiac monitor, or stepped approach) has not been well defined. Furthermore, the clinical significance of very short duration paroxysmal atrial fibrillation remains controversial. The relevance of the duration of monitoring, burden of device-detected atrial fibrillation, and its proximity to the acute ischemic stroke will require more research to define the most effective methods for stroke prevention in this patient population.

Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement.

The functional evolution of collembolan Ubx on the regulation of abdominal appendage formation.

Folsomia candida is a tiny soil-living arthropod belonging to the Collembola, which is an outgroup to Insecta. It resembles insects as having a pair of antennae and three pairs of thorax legs, while it also possesses three abdominal appendages: a ventral tube located in the first abdominal segment (A1), a retinaculum in A3, and a furca in A4. Collembolan Ubx and AbdA specify abdominal appendages, but they are unable to repress appendage marker gene Dll. The genetic basis of collembolan appendage formation and the mechanisms by which Ubx and AbdA regulate Dll transcription and appendage development remains unknown. In this study, we analysed the developmental transcriptomes of F. candida and identified candidate appendage formation genes, including Ubx (FcUbx). The expression data revealed the dominance of Dll over Ubx during the embryonic 3.5 and 4.5 days, suggesting that Ubx is deficient in suppressing Dll at early appendage formation stages. Furthermore, via electrophoretic mobility shift assays and dual luciferase assays, we found that the binding and repression capacity of FcUbx on Drosophila Dll resembles those of the longest isoform of Drosophila Ubx (DmUbx_Ib), while the regulatory mechanism of the C-terminus of FcUbx on Dll repression is similar to that of the crustacean Artemia franciscana Ubx (AfUbx), demonstrating that the function of collembolan Ubx is intermediate between that of Insecta and Crustacea. In summary, our study provides novel insights into collembolan appendage formation and sheds light on the functional evolution of Ubx. Additionally, we propose a model that collembolan Ubx regulates abdominal segments in a context-specific manner.

longfin causes cis-ectopic expression of the kcnh2a ether-a-go-go K+ channel to autonomously prolong fin outgrowth.

Organs stop growing to achieve a characteristic size and shape in scale with the body of an animal. Likewise, regenerating organs sense injury extents to instruct appropriate replacement growth. Fish fins exemplify both phenomena through their tremendous diversity of form and remarkably robust regeneration. The classic zebrafish mutant longfint2 develops and regenerates dramatically elongated fins and underlying ray skeleton. We show longfint2 chromosome 2 overexpresses the ether-a-go-go-related voltage-gated potassium channel kcnh2a. Genetic disruption of kcnh2a in cis rescues longfint2, indicating longfint2 is a regulatory kcnh2a allele. We find longfint2 fin overgrowth originates from prolonged outgrowth periods by showing Kcnh2a chemical inhibition during late stage regeneration fully suppresses overgrowth. Cell transplantations demonstrate longfint2-ectopic kcnh2a acts tissue autonomously within the fin intra-ray mesenchymal lineage. Temporal inhibition of the Ca2+-dependent phosphatase calcineurin indicates it likewise entirely acts late in regeneration to attenuate fin outgrowth. Epistasis experiments suggest longfint2-expressed Kcnh2a inhibits calcineurin output to supersede growth cessation signals. We conclude ion signaling within the growth-determining mesenchyme lineage controls fin size by tuning outgrowth periods rather than altering positional information or cell-level growth potency.

Development of Physiologically Relevant Skin Organoids from Human Induced Pluripotent Stem Cells.

The development of skin organs for studying developmental pathways, modeling diseases, or regenerative medicine purposes is a major endeavor in the field. Human induced pluripotent stem cells (hiPSCs) are successfully used to derive skin cells, but the field is still far from meeting the goal of creating skin containing appendages, such as hair follicles and sweat glands. Here, the goal is to generate skin organoids (SKOs) from human skin fibroblast or placental CD34+ cell-derived hiPSCs. With all three hiPSC lines, complex SKOs with stratified skin layers and pigmented hair follicles are generated with different efficacies. In addition, the hiPSC-derived SKOs develop sebaceous glands, touch-receptive Merkel cells, and more importantly eccrine sweat glands. Together, physiologically relevant skin organoids are developed by direct induction of embryoid body formation, along with simultaneous inactivation of transforming growth factor beta signaling, activation of fibroblast growth factor signaling, and inhibition of bone morphogenetic protein signaling pathways. The skin organoids created in this study can be used as valuable platforms for further research into human skin development, disease modeling, or reconstructive surgeries.

Prognostic Significance of Tumor-Infiltrating Lymphocytes and High-Risk Human Papillomavirus in Ocular Sebaceous Carcinoma: A Comprehensive Analysis.

High-risk human papillomavirus (hrHPV) and tumor-infiltrating lymphocytes (TILs) are known to have prognostic significance in oropharyngeal squamous cell carcinoma. However, their significance in ocular sebaceous carcinoma (OSC) remains unverified because of the rarity of the condition. This study aimed to investigate the association between clinicopathologic features, biomarkers, and hrHPV infection and their potential to predict prognosis in OSC patients. We analyzed the clinicopathologic features of 81 OSC patients from Asan Medical Center between 2000 and 2022. Seventeen biomarkers and hrHPV were examined using immunohistochemistry and DNA in situ hybridization on tissue microarray cores. hrHPV was identified in 31 cases (38.3%). Univariate analysis revealed that hrHPV infection was associated with comedonecrosis (P = .032), high Ki-67 labeling index (≥30%, P = .042), lower expression of E-cadherin (P = .033), and loss of expression of zinc finger protein 750 (P = .023). Multivariate analysis revealed that loss of expression of zinc finger protein 750 (P = .026) remained an independently associated factor for hrHPV. Progression-free survival analysis was performed on 28 patients who were continuously observed for more than 5 years. During a median follow-up duration of 86 months, recurrence or metastasis developed in 14 patients (50%) within the survival cohort, occurring at a median time of 48 months after excision. Univariate analysis indicated that recurrence or metastasis was associated with tumor size (P = .010), high TILs (≥10%; P = .025), lymphovascular invasion (P = 0.043), site of origin (P = .025), and high expression of bcl-2-associated athanogene 3 (P = .039). Multivariate analysis demonstrated that high TILs (P = .017) and site of origin (P = .025) were independent prognostic factors. The prognosis of OSC was hrHPV-independent, and a better prognosis was associated with the site of origin in the order of the gland of Zeis, meibomian gland, and multicentric site, as well as with high TILs.

Accumulated ß-catenin is associated with human atrial fibrosis and atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by ß-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of ß-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues . METHODS: We compared the difference of ß-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of ß-catenin in the development of AF was also explored in mice and primary cells. RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of ß-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, ß-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3ß (GSK-3ß) and Adenomatous Polyposis Coli (APC), which participated in the degradation of ß-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting ß-catenin expression in the AF model mice. CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that ß-catenin was associated with atrial fibrosis and AF progression.

A device-related fistula between coronary artery and left atrial appendage following left atrial appendage closure: Case presentation.

INTRODUCTION: Left atrial appendage (LAA) closure (LAAC) is considered a viable alternative to anticoagulation therapy for stroke prevention in nonvalvular atrial fibrillation, we report a case with a less common shunt resulting from a device-related coronary artery-appendage fistula (CAAF) following LAAC. METHODS AND RESULTS: A 67-year-old male with a history of LAAC was referred to our emergency room with recurrent chest pain and palpitations and was diagnosed with ischemic angina pectoris. Subsequent coronary angiography (CAG) revealed 70% in-stent restenosis and an abnormal shunt of contrast originating from the left circumflex artery (LCA) to the LAA tip which did not exist before. The restenosis was successfully dilated using a drug-coated balloon, the procedure was safely completed without pericardial effusion. The patient had been implanted with a LAmbre occluder (Lifetech Scientific Corp.) in the previous LAAC procedure. This occluder had a lobe-disk design, and the distal umbrella was not fully opened after release, particularly in the lower portion. This could make the hooks embedded on the umbrella contact the LAA wall more tightly, possibly resulting in microperforation and coincidental impingement of the LCA. The epicardial adipose and hyperplastic tissue then chronically wrapped the perforated site, prevented blood outflow into the epicardium, and ultimately formed a CAAF. CONCLUSION: CAAF is a rare complication after LAAC but may be underestimated, especially for lobe-disk designed occluders. Therefore, CAG is perhaps necessary to detect this complication.

First in man right atrial appendage implantation of a Micra leadless pacemaker.

INTRODUCTION: Pacemaker implantation can be challenging in patients with congenital heart disease. METHODS AND RESULTS: In a patient with Ebstein disease and symptomatic sinus node dysfunction, despite multiple attempts, the Micra® pacemaker could not be implanted in the severely dilated right ventricle. In that context, and after iodine injection to confirm the appropriate location, the Micra® pacemaker was successfully implanted in the right appendage at the first attempt. CONCLUSION: Despite the recent development of dedicated dual-chamber leadless pacemaker, to the best of our knowledge, this case is the first off-label Micra® implantation in a right appendage.