A new algorithm to diagnose atrial ectopic origin from multi lead ECG systems - insights from 3D virtual human atria and torso

Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms

Optimization of a high work function solution processed vanadium oxide hole-extracting layer for small molecule and polymer organic photovoltaic cells

We report a method of fabricating a high work function, solution processable vanadium oxide (V2Ox(sol)) hole-extracting layer. The atmospheric processing conditions of film preparation have a critical influence on the electronic structure and stoichiometry of the V2Ox(sol), with a direct impact on organic photovoltaic (OPV) cell performance. Combined Kelvin probe (KP) and ultraviolet photoemission spectroscopy (UPS) measurements reveal a high work function, n-type character for the thin films, analogous to previously reported thermally evaporated transition metal oxides. Additional states within the band gap of V2Ox(sol) are observed in the UPS spectra and are demonstrated using X-ray photoelectron spectroscopy (XPS) to be due to the substoichiometric nature of V2Ox(sol). The optimized V2Ox(sol) layer performance is compared directly to bare indium–tin oxide (ITO), poly(ethyleneoxythiophene):poly(styrenesulfonate) (PEDOT:PSS), and thermally evaporated molybdenum oxide (MoOx) interfaces in both small molecule/fullerene and polymer/fullerene structures. OPV cells incorporating V2Ox(sol) are reported to achieve favorable initial cell performance and cell stability attributes

Effects of persistent atrial fibrillation-induced electrical remodeling on atrial electro-mechanics – insights from a 3D model of the human atria

A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2–3months after cardio version (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodelled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished

Measuring physical activity levels in people with mild cognitive impairment or mild dementia

Measuring physical activity (PA) in people with mild cognitive impairment (MCI) or dementia can be difficult. The aim was to investigate the validity and acceptability of three different PA measurement methods.The mixed-method analysis included 49 participants with MCI or dementia who completed a daily calendar recording PA, the International Physical Activity Questionnaire (IPAQ), the LASA Physical Activity Questionnaire and wore a Misfit Shine accelerometer. The quantitative analysis showed equal completion rates for the IPAQ questionnaire and the accelerometer but a lower completion rate for the calendar. Correlations between outcome measures were moderate or strong. The qualitative analysis indicated that all measures were acceptable, though help to complete the calendars or fasten the accelerometers was required for some participants. The study supported the validity of these methods for people with MCI and mild dementia. Using accelerometers and completing calendars might increase motivation to be active for some people

Buffer gas cooling and trapping of atoms with small magnetic moments

Buffer gas cooling was extended to trap atoms with small magnetic moment (mu). For mu greater than or equal to 3mu_B, 1e12 atoms were buffer gas cooled, trapped, and thermally isolated in ultra high vacuum with roughly unit efficiency. For mu < 3mu_B, the fraction of atoms remaining after full thermal isolation was limited by two processes: wind from the rapid removal of the buffer gas and desorbing helium films. In our current apparatus we trap atoms with mu greater than or equal to 1.1mu_B, and thermally isolate atoms with mu greater than or equal to 2mu_B. Extrapolation of our results combined with simulations of the loss processes indicate that it is possible to trap and evaporatively cool mu = 1mu_B atoms using buffer gas cooling.Comment: 17 pages, 4 figure

Arrhythmogenic late Ca2+sparks in failing heart cells and their control by action potential configuration

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early afterdepolarizations (EADs) are triggered in failing heart cells. To examine EAD initiation, high-sensitivity intracellular Ca2+ measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca2+ release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca2+ release events (“late” Ca2+ sparks) during phase 2–3 of the action potential. These late Ca2+ sparks prolong the Ca2+ transient that activates contraction and can trigger propagating microscopic Ca2+ ripples, larger macroscopic Ca2+ waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca2+ sparks and their (subsequent) spatiotemporal summation into Ca2+ ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca2+ sparks provide a mechanism for EAD initiation. Computer simulations confirmed that this forms the basis of a strong oscillatory positive feedback system that can act in parallel with other purely voltage-dependent ionic mechanisms for EAD initiation. In failing heart cells, restoration of the action potential to a nonfailing phase 1 configuration improved the synchrony of excitation–contraction coupling, increased Ca2+ transient amplitude, and suppressed late Ca2+ sparks. Therapeutic control of late Ca2+ spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death

Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking

AbstractThe antiarrhythmic drug amiodarone delays cardiac repolarisation through inhibition of hERG-encoded potassium channels responsible for the rapid delayed rectifier potassium current (IKr). This study aimed to elucidate molecular determinants of amiodarone binding to the hERG channel. Whole-cell patch-clamp recordings were made at 37°C of ionic current (IhERG) carried by wild-type (WT) or mutant hERG channels expressed in HEK293 cells. Alanine mutagenesis and ligand docking were used to investigate the roles of pore cavity amino-acid residues in amiodarone binding. Amiodarone inhibited WT outward IhERG tails with a half-maximal inhibitory concentration (IC50) of ∼45nM, whilst inward IhERG tails in a high K+ external solution ([K+]e) of 94mM were blocked with an IC50 of 117.8nM. Amiodarone’s inhibitory action was contingent upon channel gating. Alanine-mutagenesis identified multiple residues directly or indirectly involved in amiodarone binding. The IC50 for the S6 aromatic Y652A mutation was increased to ∼20-fold that of WT IhERG, similar to the pore helical mutant S624A (∼22-fold WT control). The IC50 for F656A mutant IhERG was ∼17-fold its corresponding WT control. Computational docking using a MthK-based hERG model differentiated residues likely to interact directly with drug and those whose Ala mutation may affect drug block allosterically. The requirements for amiodarone block of aromatic residues F656 and Y652 within the hERG pore cavity are smaller than for other high affinity IhERG inhibitors, with relative importance to amiodarone binding of the residues investigated being S624A∼Y652A>F656A>V659A>G648A>T623A

Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm‐1 scorpion toxin

The scorpion toxin peptide BeKm‐1 was synthesised by fluorenylmethoxycarbonyl solid phase chemistry and folded by air oxidation. The peptide's effects on heterologous human ether‐a‐go‐go‐related gene potassium current (I HERG) in HEK293 cells were assessed using 'whole‐cell' patch clamp. Blockade of I HERG by BeKm‐1 was concentration‐dependent, temperature‐dependent, and rapid in onset and reversibility. Blockade also exhibited inverse voltage dependence, inverse dependence on duration of depolarisation, and reverse use‐ and frequency‐dependence. Blockade by BeKm‐1 and recombinant ergtoxin, another scorpion toxin known to block HERG, differed in their recovery from HERG current inactivation elicited by strong depolarisation and in their ability to block HERG when the channels were already activated. We conclude that synthetic BeKm‐1 toxin blocks HERG preferentially through a closed (resting) state channel blockade mechanism, although some open channel blockade also occurs