Background: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation (OAC) for thromboembolic risk reduction in patients with non-valvular atrial fibrillation (NVAF). 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 evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with NVAF in whom OAC is indicated, but who have an appropriate rationale to seek a non-pharmaceutical alternative. Methods: This was a prospective, non-randomized, multi-center FDA study. The primary safety endpoint was the occurrence of one of the following events within 7 days post-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 endpoint was the incidence of effective LAA closure (peri-device flow ≤5mm), 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{plus minus}8.6 years and the mean CHA2DS2-VASc score was 4.2{plus minus}1.5. The incidence of the primary safety endpoint was 0.5% with a one-sided 95% upper confidence interval (CI) of 1.6%, meeting the performance goal (PG) of 4.2% (P<0.0001). The incidence of the primary effectiveness endpoint was 100%, with a onesided 95% lower CI of 99.1%, again meeting the PG of 97.0% (P<0.0001). Device-related thrombus was reported in 7 patients, no patients experienced pericardial effusion requiring open cardiac surgery, and there were no device embolizations. 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. Clinical Trial Registration: URL https://clinicaltrials.gov Unique Identifier NCT02702271

End-stage heart failure (HF) is characterized by changes in conduction velocity (CV) that predispose to arrhythmias. Here, we investigate the time course of conduction changes with respect to alterations in connexin 43 (Cx43) properties and mechanical function during the development of HF. We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21 days of rapid pacing to produce variable degrees of remodeling. CV is compared with an index of mechanical function [left ventricular end-diastolic pressure (LVEDP)] and with dynamic changes in the expression, distribution, and phosphorylation of Cx43. In contrast to repolarization, CV was preserved during early stages of remodeling (3 and 7 days) and significantly reduced at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained downregulation of pan-Cx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated Cx43 isoform to over twofold baseline levels in end-stage HF, and a late abrupt increase in pan-Cx43, but not dephosphorylated Cx43, lateralization. These data demonstrate that 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of pan-Cx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event that coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.

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Background - The limited effectiveness of endocardial catheter ablation (CA) for persistent and long-standing persistent atrial fibrillation (Ps/LSP-AF) treatment led to the development of a minimally-invasive epicardial/endocardial ablation approach (Hybrid Convergent) to achieve a more comprehensive lesion set with durable transmural lesions. The multi-center randomized controlled CONVERGE trial (NCT01984346) evaluated the safety of Hybrid Convergent and compared its effectiveness to CA for Ps/LSP-AF treatment. Methods - One-hundred fifty-three patients were randomized 2:1 to Hybrid Convergent vs. CA. Primary effectiveness was freedom from AF/AFL/AT absent new/increased dosage of previously failed/intolerant class I/III anti-arrhythmic drugs (AADs) through 12-months. Primary safety was major adverse events through 30 days. CONVERGE permitted left atrium size up to 6cm and imposed no limits on AF duration, making it the only ablation trial to substantially include LSP-AF i.e. 42% patients with LSP-AF. Results - Of 149 evaluable patients at 12 months, primary effectiveness was achieved in 67.7% (67/99) patients with Hybrid Convergent and 50.0% (25/50) with CA (p=0.036) on/off previously failed AADs and in 53.5% (53/99) versus 32.0% (16/50) (p=0.0128) respectively off AADs. At 18-months using 7-day Holter, 74.0% (53/72) Hybrid Convergent and 55% (23/42) CA patients experienced ≥90% AF burden reduction. A total of 2.9% (3/102) patients had primary safety events within 7 days, and 4.9% (5/102) between 8-30 days post-procedure. No deaths, cardiac perforations or atrioesophageal fistulas occurred. All but one primary safety event resolved. Conclusions - The Hybrid Convergent procedure has superior effectiveness compared to the CA for the treatment of Ps/LSP-AF.