Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders.

AIMS Incomplete left atrial appendage occlusion (LAAO) due to peri-device leak (PDL) is a limitation of the therapy. The Amulet IDE trial is the largest randomized head-to-head trial comparing the Amulet and Watchman 2.5 LAAO devices with fundamentally different designs. The predictors and mechanistic factors impacting differences in PDLs within the Amulet IDE trial are assessed in the current analysis. METHODS AND RESULTS An independent core lab analysed all images for the presence or absence of severe PDL (>5 mm). The incidence, mechanistic factors, predictors using propensity score-matched controls, and evolution of severe PDLs through 18 months were assessed. Of the 1878 patients randomized in the trial, the Amulet occluder had significantly fewer severe PDLs than the Watchman device at 45 days (1.1 vs. 3.2%, P < 0.001) and 12 months (0.1 vs. 1.1%, P < 0.001). Off-axis deployment or missed lobes were leading mechanistic PDL factors in each device group. Larger left atrial appendage (LAA) dimensions including orifice diameter, landing zone diameter, and depth predicted severe PDL with the Watchman device, with no significant anatomical limitations noted with the Amulet occluder. Procedural and device implant predictors were found with the Amulet occluder attributed to the learning curve with the device. A majority of Watchman device severe PDLs did not resolve over time through 18 months. CONCLUSION The dual-occlusive Amplatzer Amulet LAA occluder provided improved LAA closure compared with the Watchman 2.5 device. Predictors and temporal observations of severe PDLs were identified in the Amulet IDE trial. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov Unique identifier NCT02879448

A Computational Model for the Electrostatic Sequestration of PI(4,5)P(2) by Membrane-Adsorbed Basic Peptides

The multivalent acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) plays a key role in many biological processes. Recent studies show that unstructured clusters of basic residues from a number of peripheral proteins can laterally sequester PI(4,5)P(2) in membranes. Specifically, experiments suggest that the basic effector domain of the myristoylated alanine-rich C kinase substrate (MARCKS), or a peptide corresponding to this domain, MARCKS(151–175), sequesters several PI(4,5)P(2) and that this sequestration is due to nonspecific electrostatic interactions. Here, we use the finite difference Poisson-Boltzmann method to test this hypothesis by calculating the electrostatic free energy of lateral sequestration of PI(4,5)P(2) by membrane-adsorbed basic peptides: Lys-7, Lys-13, and FA-MARCKS(151–175), a peptide based on MARCKS(151–175). In agreement with experiments, we find that the electrostatic free energy becomes more favorable when: 1), Lys-13 and FA-MARCKS(151–175) sequester several PI(4,5)P(2); 2), the linear charge density of the basic peptide increases; 3), the mol percent monovalent acidic lipid in the membrane decreases; and 4), the ionic strength of the solution decreases. In addition, the electrostatic sequestration free energy is in excess of the entropic penalty associated with localizing PI(4,5)P(2). Our calculations, thus, provide a structural and quantitative description of the observed interaction of PI(4,5)P(2) with membrane-adsorbed basic sequences

A clinical feasibility study of atrial and ventricular electromechanical wave imaging

BACKGROUND: Cardiac Resynchronization Therapy (CRT) and atrial ablation currently lack a noninvasive imaging modality for reliable treatment planning and monitoring. Electromechanical Wave Imaging (EWI) is an ultrasound-based method that has previously been shown to be capable of noninvasively and transmurally mapping the activation sequence of the heart in animal studies by estimating and imaging the electromechanical wave, i.e., the transient strains occurring in response to the electrical activation, at both very high temporal and spatial resolution. OBJECTIVE: Demonstrate the feasibility of noninvasive transthoracic EWI for mapping the activation sequence during different cardiac rhythms in humans. METHODS: EWI was performed in CRT patients with a left bundle-branch block (LBBB), during sinus rhythm, left-ventricular pacing, and right-ventricular pacing and in atrial flutter (AFL) patients before intervention and correlated with results from invasive intracardiac electrical mapping studies during intervention. Additionally, the feasibility of single-heartbeat EWI at 2000 frames/s, is demonstrated in humans for the first time in a subject with both AFL and right bundle-branch-block. RESULTS: The electromechanical activation maps demonstrated the capability of EWI to localize the pacing sites and characterize the LBBB activation sequence transmurally in CRT patients. In AFL patients, the propagation patterns obtained with EWI were in agreement with results obtained from invasive intracardiac mapping studies. CONCLUSION: Our findings demonstrate the potential capability of EWI to aid in monitoring and follow-up of patients undergoing CRT pacing therapy and atrial ablation with preliminary validation in vivo

Membrane-Bound Basic Peptides Sequester Multivalent (PIP(2)), but Not Monovalent (PS), Acidic Lipids

Several biologically important peripheral (e.g., myristoylated alanine-rich C kinase substrate) and integral (e.g., the epidermal growth factor receptor) membrane proteins contain clusters of basic residues that interact with acidic lipids in the plasma membrane. Previous measurements demonstrate that the polyvalent acidic lipid phosphatidylinositol 4,5-bisphosphate is bound electrostatically (i.e., sequestered) by membrane-adsorbed basic peptides corresponding to these clusters. We report here three experimental observations that suggest monovalent acidic lipids are not sequestered by membrane-bound basic peptides. 1), Binding of basic peptides to vesicles does not decrease when the temperature is lowered below the fluid-to-gel phase transition. 2), The binding energy of Lys-13 to lipid vesicles increases linearly with the fraction of monovalent acidic lipids. 3), Binding of basic peptides to vesicles produces no self-quenching of fluorescent monovalent acidic lipids. One potential explanation for these results is that membrane-bound basic peptides diffuse too rapidly for the monovalent lipids to be sequestered. Indeed, our fluorescence correlation spectroscopy measurements show basic peptides bound to phosphatidylcholine/phosphatidylserine membranes have a diffusion coefficient approximately twofold higher than that of lipids, and those bound to phosphatidylcholine/phosphatidylinositol 4,5-bisphosphate membranes have a diffusion coefficient comparable to that of lipids

Assessing the atrial electromechanical coupling during atrial focal tachycardia, flutter, and fibrillation using electromechanical wave imaging in humans

Minimally-invasive treatments of cardiac arrhythmias such as radio-frequency ablation are gradually gaining in importance in clinical practice but still lack a noninvasive imaging modality which provides insight into the source or focus of an arrhythmia. Cardiac deformations imaged at high temporal and spatial resolution can be used to elucidate the electrical activation sequence in normal and paced human subjects non-invasively and could potentially aid to better plan and monitor ablation-based arrhythmia treatments. In this study, a novel ultrasound-based method is presented that can be used to quantitatively characterize focal and reentrant arrhythmias. Spatio-temporal maps of the full-view of the atrial and ventricular mechanics were obtained in a single heartbeat, revealing with otherwise unobtainable detail the electromechanical patterns of atrial flutter, fibrillation, and tachycardia in humans. During focal arrhythmias such as premature ventricular complex and focal atrial tachycardia, the previously developed electromechanical wave imaging methodology is hereby shown capable of identifying the location of the focal zone and the subsequent propagation of cardiac activation. During reentrant arrhythmias such as atrial flutter and fibrillation, Fourier analysis of the strains revealed highly correlated mechanical and electrical cycle lengths and propagation patterns. High frame rate ultrasound imaging of the heart can be used non-invasively and in real time, to characterize the lesser-known mechanical aspects of atrial and ventricular arrhythmias, also potentially assisting treatment planning for intraoperative and longitudinal monitoring of arrhythmias