Search

Background: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation for thromboembolic risk reduction in patients with nonvalvular atrial fibrillation. Since regulatory approval in 2015, the WATCHMAN device has been the only LAA closure device available for clinical use in the United States. The PINNACLE FLX study (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the Watchman FLX LAA Closure Technology) evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with nonvalvular atrial fibrillation in whom oral anticoagulation is indicated, but who have an appropriate rationale to seek a nonpharmaceutical alternative. Methods: This was a prospective, nonrandomized, multicenter US Food and Drug Administration study. The primary safety end point was the occurrence of one of the following events within 7 days after the procedure or by hospital discharge, whichever was later: death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery. The primary effectiveness end point was the incidence of effective LAA closure (peri-device flow ≤5 mm), as assessed by the echocardiography core laboratory at 12-month follow-up. Results: A total of 400 patients were enrolled. The mean age was 73.8±8.6 years and the mean CHA 2 DS 2 -VASc score was 4.2±1.5. The incidence of the primary safety end point was 0.5% with a 1-sided 95% upper CI of 1.6%, meeting the performance goal of 4.2% ( P P Conclusions: LAA closure with this next-generation LAA closure device was associated with a low incidence of adverse events and a high incidence of anatomic closure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02702271. more...

INTRODUCTION Gap junctions (GJs) mediate electrical coupling between cardiomyocytes, and are required for coordinated electrical activation and contraction of the heart. GJs are remodeled in diseased myocardium, resulting in impaired intercellular coupling and a predisposition to life threatening arrhythmias. To understand the mechanisms of GJ remodeling in heart failure (HF), we examined the ultrastructure of GJs in failing canine myocardium. METHODS and RESULTS Using transmission electron microscopy, we observed the formation of GJs between lateral membranes of ventricular myocytes in rapid pacing induced heart failure (HF) in dogs. Lateral GJs exhibited complex membrane bending and extensive internalization. Lateral GJs were frequently adjacent to mitochondria and internalized GJs often formed concentric ring structures surrounding cellular debris. Internalized GJ membranes were associated with multi-lamellar membrane structures, with features characteristic of autophagosomes. Connexin43 (Cx43) and the autophagosome marker GFP-LC3 were extensively co-localized when expressed in HeLa cells. A hyperphosphorylated form of Cx43 previously associated with GJ degradation co-fractionated with LC3-II (autophagosome targeted form) in a Triton-insoluble and buoyant fraction of ventricular tissue. The hyperphosphorylated/buoyant population of Cx43 as well as LC3-II were both significantly increased (n=5 each, p=0.011 and p=0.016 respectively), and whole tissue levels of Cx43 were significantly decreased (n=5, p=0.01), in pacing-induced HF. CONCLUSION We show that structurally heterogeneous GJs are present at the lateral membranes of cardiomyocytes in HF, suggesting aberrant targeting of GJs. Internalized GJs are degraded via autophagy, which involves a hyperphosphorylated form of Cx43, and is enhanced in HF. These findings reveal a novel pathway of GJ targeting and degradation in HF, and suggest potential therapeutic targets for HF-related conduction slowing and arrhythmias. more...