Background Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types. Methods Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro. Results In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model ( Tbx5 +/− ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. Conclusions This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.
The significant mismatch of mechanical properties between the implanted medical device and biological tissue is prone to cause wear and even perforation. In addition, the limited biocompatibility and nondegradability of commercial Nitinol-based occlusion devices can easily lead to other serious complications, such as allergy and corrosion. The present study aims to develop a 4D printed patient-specific absorbable left atrial appendage occluder (LAAO) that can match the deformation of left atrial appendage (LAA) tissue to reduce complications. The desirable bioinspired network is explored by iterative optimization to mimic the stress–strain curve of LAA tissue and LAAOs are designed based on the optimal network. In vitro degradation tests are carried out to evaluate the effects of degradation on mechanical properties. In addition, 48 weeks of long-term subcutaneous implantation of the occluder shows favorable biocompatibility, and the 20-cycle compression test demonstrates outstanding durability of LAAO. Besides, a rapid, complete, and remote-controlled 4D transformation process of LAAO is achieved under the trigger of the magnetic field. The deployment of the LAAO in an isolated swine heart initially exhibits its feasibility for transcatheter LAA occlusion. To the best of our knowledge, this is the first demonstration of the 4D printed LAA occlusion device. It is worth noting that the bioinspired design concept is not only applicable to occlusion devices, but also to many other implantable medical devices, which is conducive to reducing complications, and a broad range of appealing application prospects can be foreseen.
The left atrial appendage (LAA) occluder is an important medical device for closing the LAA and preventing stroke. The device-related thrombus (DRT) prevents the implantation of the occluder in exerting the desired therapeutic effect, which is primarily caused by the delayed endothelialization of the occluder. Functional coatings are an effective strategy for accelerating the endothelialization of occluders. However, the occluder surface area is particularly large and structurally complex, and the device is subjected to a large shear friction in the sheath during implantation, which poses a significant challenge to the coating. Herein, a hydrogel coating by the in situ UV-triggered polymerization of double-network polyelectrolytes is reported. The findings reveal that the double network and electrostatic interactions between the networks resulted in excellent mechanical properties of the hydrogel coating. The sulfonate and Arg-Gly-Asp (RGD) groups in the coating promoted hemocompatibility and endothelial growth of the occluder, respectively. The coating significantly accelerated the endothelialization of the LAA occluder in a canine model is further demonstrated. This study has potential clinical benefits in reducing both the incidence of DRT and the postoperative anticoagulant course for LAA closure.
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