Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.

AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.

Automation bias: decision making and performance in high-tech cockpits.

Automated aids and decision support tools are rapidly becoming indispensable tools in high-technology cockpits and are assuming increasing control of"cognitive" flight tasks, such as calculating fuel-efficient routes, navigating, or detecting and diagnosing system malfunctions and abnormalities. This study was designed to investigate automation bias, a recently documented factor in the use of automated aids and decision support systems. The term refers to omission and commission errors resulting from the use of automated cues as a heuristic replacement for vigilant information seeking and processing. Glass-cockpit pilots flew flight scenarios involving automation events or opportunities for automation-related omission and commission errors. Although experimentally manipulated accountability demands did not significantly impact performance, post hoc analyses revealed that those pilots who reported an internalized perception of "accountability" for their performance and strategies of interaction with the automation were significantly more likely to double-check automated functioning against other cues and less likely to commit errors than those who did not share this perception. Pilots were also lilkely to erroneously "remember" the presence of expected cues when describing their decision-making processes.

Effects of workload preview on task scheduling during simulated instrument flight.

Our study examined pilot scheduling behavior in the context of simulated instrument flight. Over the course of the flight, pilots flew along specified routes while scheduling and performing several flight-related secondary tasks. The first phase of flight was flown under low-workload conditions, whereas the second phase of flight was flown under high-workload conditions in the form of increased turbulence and a disorganized instrument layout. Six pilots were randomly assigned to each of three workload preview groups. Subjects in the no-preview group were not given preview of the increased-workload conditions. Subjects in the declarative preview group were verbally informed of the nature of the flight workload manipulation but did not receive any practice under the high-workload conditions. Subjects in the procedural preview group received the same instructions as the declarative preview group but also flew half of the practice flight under the high-workload conditions. The results show that workload preview fostered efficient scheduling strategies. Specifically, those pilots with either declarative or procedural preview of future workload demands adopted an efficient strategy of scheduling more of the difficult secondary tasks during the low-workload phase of flight. However, those pilots given a procedural preview showed the greatest benefits in overall flight performance.