Biophysics and electrophysiology of pulsed field ablation in normal and infarcted porcine cardiac ventricular tissue.

Pulsed Field Ablation (PFA) is a new ablation method being rapidly adopted for treatment of atrial fibrillation, which shows advantages in safety and efficiency over radiofrequency and cryo-ablation. In this study, we used an in vivo swine model (10 healthy and 5 with chronic myocardial infarct) for ventricular PFA, collecting intracardiac electrograms, electro-anatomical maps, native T1-weighted and late gadolinium enhancement MRI, gross pathology, and histology. We used 1000-1500 V pulses, with 1-16 pulse trains to vary PFA dose.

Arrhythmogenicity of monophasic and biphasic PFA waveforms in a porcine model.

Objective: The potential risk of inducing ventricular arrhythmias was explored by employing pulsed field ablation (PFA) through the administration of both monophasic and biphasic waveform deliveries.

Methods: PFA was applied to specific locations in the right ventricle (RV, n = 5 sites) in swine (n = 2), utilizing identical settings with consistent amplitude, pulse width, and a number of pulses for both monophasic and biphasic waveforms. PFA deliveries were precisely timed in 10-ms intervals across the entire T wave.

The importance of electrode-tissue proximity in creating pulsed field ablation lesions: insights from a sub-acute preclinical model.

Background: We sought to evaluate the anatomic and functional lesion development over time at different atrial sites immediately following delivery of pulsed field ablation (PFA).

Methods: Using a porcine model, PFA ablations were performed in the superior vena cava (SVC), right atrial lateral wall (RA), left atrial appendage (LAA), and right superior pulmonary vein (RSPV) using four different PFA profiles. Mapping was done sequentially in 5-20-min increments up to 280-min post lesion delivery for low voltage area (LVA) assessment and conduction velocity.

The Effects of Interphase and Interpulse Delays and Pulse Widths on Induced Muscle Contractions, Pain and Therapeutic Efficacy in Electroporation-Based Therapies.

Electroporation is used in medicine for drug and gene delivery, and as a nonthermal ablation method in tumor treatment and cardiac ablation. Electroporation involves delivering high-voltage electric pulses to target tissue; however, this can cause effects beyond the intended target tissue like nerve stimulation, muscle contractions and pain, requiring use of sedatives or anesthetics. It was previously shown that adjusting pulse parameters may mitigate some of these effects, but not how these adjustments would affect electroporation's efficacy.

Determination of lethal electric field threshold for pulsed field ablation in perfused porcine and human hearts.

Introduction: Pulsed field ablation is an emerging modality for catheter-based cardiac ablation. The main mechanism of action is irreversible electroporation (IRE), a threshold-based phenomenon in which cells die after exposure to intense pulsed electric fields. Lethal electric field threshold for IRE is a tissue property that determines treatment feasibility and enables the development of new devices and therapeutic applications, but it is greatly dependent on the number of pulses and their duration.

Characterization of Experimentally Observed Complex Interplay between Pulse Duration, Electrical Field Strength, and Cell Orientation on Electroporation Outcome Using a Time-Dependent Nonlinear Numerical Model.

Electroporation is a biophysical phenomenon involving an increase in cell membrane permeability to molecules after a high-pulsed electric field is applied to the tissue. Currently, electroporation is being developed for non-thermal ablation of cardiac tissue to treat arrhythmias. Cardiomyocytes have been shown to be more affected by electroporation when oriented with their long axis parallel to the applied electric field.

A Multiscale Computational Model of Skeletal Muscle Electroporation Validated Using In Situ Porcine Experiments.

Objective: The goal of our study was to determine the importance of electric field orientation in an anisotropic muscle tissue for the extent of irreversible electroporation damage by means of an experimentally validated mathematical model.

Methods: Electrical pulses were delivered to porcine skeletal muscle in vivo by inserting needle electrodes so that the electric field was applied in direction either parallel or perpendicular to the direction of the muscle fibres. Triphenyl tetrazolium chloride staining was used to determine the shape of the lesions.

Effect of contact force on pulsed field ablation lesions in porcine cardiac tissue.

Introduction: Contact force has been used to titrate lesion formation for radiofrequency ablation. Pulsed field ablation (PFA) is a field-based ablation technology for which limited evidence on the impact of contact force on lesion size is available.

Methods: Porcine hearts (n = 6) were perfused using a modified Langendorff set-up.

Reversible and Irreversible Effects of Electroporation on Contractility and Calcium Homeostasis in Isolated Cardiac Ventricular Myocytes.

Background: Irreversible electroporation is an energy form utilizing high-voltage pulsed electric field, leading to cellular homeostasis disruption and cell death. Recently, irreversible electroporation has shown promising results for the treatment of cardiac arrhythmias. However, reversible and irreversible effects of pulsed electric field on cardiac myocytes remain poorly understood.

Effects of Electrode-Tissue Proximity on Cardiac Lesion Formation Using Pulsed Field Ablation.

Background: Pulsed field ablation (PFA) is a novel energy modality for treatment of cardiac arrhythmias. The impact of electrode-tissue proximity on lesion formation by PFA has not been conclusively assessed. The objective of this investigation was to evaluate the effects of electrode-tissue proximity on cardiac lesion formation with a biphasic, bipolar PFA system.

Characterization of Phrenic Nerve Response to Pulsed Field Ablation.

Background: Phrenic nerve palsy is a well-known complication of cardiac ablation, resulting from the application of direct thermal energy. Emerging pulsed field ablation (PFA) may reduce the risk of phrenic nerve injury but has not been well characterized.

Methods: Accelerometers and continuous pacing were used during PFA deliveries in a porcine model.

Point absorbers in Advanced LIGO.

Small, highly absorbing points are randomly present on the surfaces of the main interferometer optics in Advanced LIGO. The resulting nanometer scale thermo-elastic deformations and substrate lenses from these micron-scale absorbers significantly reduce the sensitivity of the interferometer directly though a reduction in the power-recycling gain and indirect interactions with the feedback control system. We review the expected surface deformation from point absorbers and provide a pedagogical description of the impact on power buildup in second generation gravitational wave detectors (dual-recycled Fabry-Perot Michelson interferometers).

Particle-based Ising model.

We characterize equilibrium properties and relaxation dynamics of a two-dimensional lattice containing, at each site, two particles connected by a double-well potential (dumbbell). Dumbbells are oriented in the orthogonal direction with respect to the lattice plane and interact with each other through a Lennard-Jones potential truncated at the nearest neighbor distance. We show that the system's equilibrium properties are accurately described by a two-dimensional Ising model with an appropriate coupling constant.

Microcanonical coarse-graining of the kinetic Ising model.

We propose a scheme for coarse-graining the dynamics of the 2-D kinetic Ising model onto the microcanonical ensemble. At subcritical temperatures, 2-D and higher-dimensional Ising lattices possess two basins of attraction separated by a free energy barrier. Projecting onto the microcanonical ensemble has the advantage that the dependence of the crossing rate constant on environmental conditions can be obtained from a single Monte Carlo trajectory.

Linkage analysis reveals allosteric coupling in Kir2.1 channels.

Potassium-selective inward rectifier (Kir) channels are a class of membrane proteins necessary for maintaining stable resting membrane potentials, controlling excitability, and shaping the final repolarization of action potentials in excitable cells. In addition to the strong inward rectification of the ionic current caused by intracellular blockers, Kir2.1 channels possess "weak" inward rectification observed in inside-out patches after prolonged washout of intracellular blockers.

Effect of Charge Delivery on Thromboembolism During Radiofrequency Ablation in Canines.

Objectives: This study investigated whether delivering negative charge to catheter tips reduces thromboembolism during catheter ablation.

Background: Radiofrequency (RF) ablation prevents atrial fibrillation that can cause stroke or death. However, ablation itself can cause stroke (2%) or silent ischemia (2% to 41%), possibly via particulate debris that embolizes after coagulum adherence to catheter surfaces.

Prospects for Detecting Gravitational Waves at 5 Hz with Ground-Based Detectors.

We propose an upgrade to Advanced LIGO (aLIGO), named LIGO-LF, that focuses on improving the sensitivity in the 5-30 Hz low-frequency band, and we explore the upgrade's astrophysical applications. We present a comprehensive study of the detector's technical noises and show that with technologies currently under development, such as interferometrically sensed seismometers and balanced-homodyne readout, LIGO-LF can reach the fundamental limits set by quantum and thermal noises down to 5 Hz. These technologies are also directly applicable to the future generation of detectors.

Featured Article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts.

Ischemic preconditioning has been utilized to protect the heart from ischemia prior to ischemia onset, whereas postconditioning is employed to minimize the consequences of ischemia at the onset of reperfusion. The underlying mechanisms and pathways of ischemic pre- and postconditioning continue to be investigated as therapeutic targets. We evaluated the administration of a delta opioid agonist or cariporide on various parameters associated with myocardial reperfusion injury upon reperfusion of isolated porcine hearts.

The α2δ-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials.

Excitation-evoked calcium influx across cellular membranes is strictly controlled by voltage-gated calcium channels (CaV), which possess four distinct voltage-sensing domains (VSDs) that direct the opening of a central pore. The energetic interactions between the VSDs and the pore are critical for tuning the channel's voltage dependence. The accessory α2δ-1 subunit is known to facilitate CaV1.

Self-amplified lock of an ultra-narrow linewidth optical cavity.

High finesse optical cavities are an essential tool in modern precision laser interferometry. The incident laser field is often controlled and stabilized with an active feedback system such that the field resonates in the cavity. The Pound-Drever-Hall reflection locking technique is a convenient way to derive a suitable error signal.

Observation of Parametric Instability in Advanced LIGO.

Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this Letter, we describe the first observation of parametric instability in a gravitational wave detector, and the means by which it has been removed as a barrier to progress.

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel.

Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca(2+) entry are thought to be functions of voltage-gated calcium (CaV) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown.

Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure.

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116).

Modeling ion channels: past, present, and future.

Ion channels are membrane-bound enzymes whose catalytic sites are ion-conducting pores that open and close (gate) in response to specific environmental stimuli. Ion channels are important contributors to cell signaling and homeostasis. Our current understanding of gating is the product of 60 plus years of voltage-clamp recording augmented by intervention in the form of environmental, chemical, and mutational perturbations.