Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re-entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF. A novel biophysical model of the canine atria was used that integrates stochastic, spontaneous subcellular Ca2+ release events (SCRE) with regional electrophysiological heterogeneity in ionic properties and a detailed three-dimensional model of atrial anatomy, microarchitecture and patchy fibrosis. Simulations highlighted the importance of the smaller inward rectifier potassium current (IK1 ) in PV cells compared to the surrounding atria, which enabled SCRE more readily to result in delayed-afterdepolarisations that induced triggered activity. There was a leftward shift in the dependence of the probability of triggered activity on sarcoplasmic reticulum Ca2+ load. This feature was accentuated in 3D tissue compared to single cells (Δ half-maximal [Ca2+ ]SR  = 58 µM vs. 22 µM). In 3D atria incorporating electrical heterogeneity, excitations preferentially emerged from the PV region. These triggered focal excitations resulted in transient re-entry in the left atrium. Addition of fibrotic patches promoted localised emergence of focal excitations and wavebreaks that had a more substantial impact on generating AF-like patterns than the PVs. Thus, a reduced IK1 , less negative resting membrane potential, and fibrosis-induced changes of the electrotonic load all contribute to the emergence of complex excitation patterns from spontaneous focal triggers. KEY POINTS: Focal excitations in the atria are most commonly associated with the pulmonary veins, but the mechanisms for this localisation are yet to be elucidated. We applied a multi-scale computational modelling approach to elucidate the mechanisms underlying such localisations. Myocytes in the pulmonary vein region of the atria have a less negative resting membrane potential and reduced time-independent potassium current; we demonstrate that both of these factors promote triggered activity in single cells and tissues. The less negative resting membrane potential also contributes to heterogeneous inactivation of the fast sodium current, which can enable re-entrant-like excitation patterns to emerge without traditional conduction block.

Multi-scale approaches for the simulation of cardiac electrophysiology: I - Sub-cellular and stochastic calcium dynamics from cell to organ.

Computational models of the heart at multiple spatial scales, from sub-cellular nanodomains to the whole-organ, are a powerful tool for the simulation of cardiac electrophysiology. Application of these models has provided remarkable insight into the normal and pathological functioning of the heart. In these two articles, we present methods for modelling cardiac electrophysiology at all of these spatial scales. In part one, presented here, we discuss methods and approaches for modelling sub-cellular calcium dynamics at the whole-cell and organ scales, valuable for modelling excitation-contraction coupling and mechanisms of arrhythmia triggers.

Multi-scale approaches for the simulation of cardiac electrophysiology: II - Tissue-level structure and function.

Computational models of the heart, from cell-level models, through one-, two- and three-dimensional tissue-level simplifications, to biophysically-detailed three-dimensional models of the ventricles, atria or whole heart, allow the simulation of excitation and propagation of this excitation, and have provided remarkable insight into the normal and pathological functioning of the heart. In this article we present equations for modelling cellular excitation (i.e. the cell action potential) from both a phenomenological and a biophysical perspective. Hodgkin-Huxley formalism is discussed, along with the current generation of biophysically-detailed cardiac cell models. Alternative Markovian formulations for modelling ionic currents are also presented. Equations describing propagation of this cellular excitation, through one-, two- and three-dimensional idealised or realistic tissues, are then presented. For all types of model, from cell to tissue, methods for discretisation and integration of the underlying equations are discussed. The article finishes with a discussion of two tissue-level experimental imaging techniques - diffusion tensor magnetic resonance imaging and optical imaging - that can be used to provide data for parameterisation and validation of cell- and tissue-level cardiac models.

Arrhythmia mechanisms and spontaneous calcium release: Bi-directional coupling between re-entrant and focal excitation.

Spontaneous sub-cellular calcium release events (SCRE) are conjectured to promote rapid arrhythmias associated with conditions such as heart failure and atrial fibrillation: they can underlie the emergence of spontaneous action potentials in single cells which can lead to arrhythmogenic triggers in tissue. The multi-scale mechanisms of the development of SCRE into arrhythmia triggers, and their dynamic interaction with the tissue substrate, remain elusive; rigorous and simultaneous study of dynamics from the nanometre to the centimetre scale is a major challenge. The aim of this study was to develop a computational approach to overcome this challenge and study potential bi-directional coupling between sub-cellular and tissue-scale arrhythmia phenomena. A framework comprising a hierarchy of computational models was developed, which includes detailed single-cell models describing spatio-temporal calcium dynamics in 3D, efficient non-spatial cell models, and both idealised and realistic tissue models. A phenomenological approach was implemented to reproduce SCRE morphology and variability in the efficient cell models, comprising the definition of analytical Spontaneous Release Functions (SRF) whose parameters may be randomly sampled from appropriate distributions in order to match either the 3D cell models or experimental data. Pro-arrhythmogenic pacing protocols were applied to initiate re-entry and promote calcium overload, leading to the emergence of SCRE. The SRF accurately reproduced the dynamics of SCRE and its dependence on environment variables under multiple different conditions. Sustained re-entrant excitation promoted calcium overload, and led to the emergence of focal excitations after termination. A purely functional mechanism of re-entry and focal activity localisation was demonstrated, related to the unexcited spiral wave core. In conclusion, a novel approach has been developed to dynamically model SCRE at the tissue scale, which facilitates novel, detailed multi-scale mechanistic analysis. It was revealed that complex re-entrant excitation patterns and SCRE may be bi-directionally coupled, promoting novel mechanisms of arrhythmia perpetuation.

Investigation of the Role of Myocyte Orientations in Cardiac Arrhythmia Using Image-Based Models.

Cardiac electrical excitation-propagation is influenced by myocyte orientations (cellular organization). Quantitatively understanding this relationship presents a significant research challenge, especially during arrhythmias in which excitation patterns become complex. Tissue-scale simulations of cardiac electrophysiology, incorporating both dynamic action potential behavior and image-based myocardial architecture, provide an approach to investigate three-dimensional (3D) propagation of excitation waves in the heart. In this study, we aimed to assess the importance of natural variation in myocyte orientations on cardiac arrhythmogenesis using 3D tissue electrophysiology simulations. Three anatomical models (i.e., describing myocyte orientations) of healthy rat ventricles-obtained using diffusion tensor imaging at 100 µm resolution-were registered to a single biventricular geometry (i.e., a single cardiac shape), in which the myocyte orientations could be represented by each of the diffusion tensor imaging data sets or by an idealized rule-based description. The Fenton-Karma cellular excitation model was modified to reproduce rat ventricular action potential duration restitution to create reaction-diffusion cardiac electrophysiology models. Over 250 3D simulations were performed to investigate the effects of myocyte orientations on the following: 1) ventricular activation, 2) location-dependent arrhythmia induction via rapid pacing, and 3) dynamics of re-entry averaged over multiple episodes. It was shown that 1) myocyte orientation differences manifested themselves in local activation times, but the influence on total activation time was small; 2) differences in myocyte orientations could critically affect the inducibility and persistence of arrhythmias for specific stimulus-location/cycle-length combinations; and 3) myocyte orientations alone could be an important determinant of scroll wave break, although no significant differences were observed in averaged arrhythmia dynamics between the four myocyte orientation scenarios considered. Our results show that myocyte orientations are an important determinant of arrhythmia inducibility, persistence, and scroll wave break. These findings suggest that where specificity is desired (for example, when predicting location-dependent, patient-specific arrhythmia inducibility), subject-specific myocyte orientations may be important.

Dynamic clamping human and rabbit atrial calcium current: narrowing ICaL window abolishes early afterdepolarizations.

KEY POINTS: Early-afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca2+ current (ICaL ) in its 'window region' voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood. Atrial cells were obtained from consenting patients undergoing heart surgery, as well as from rabbits. ICaL was blocked with nifedipine and then a hybrid patch clamp/mathematical-modelling technique, 'dynamic clamping', was used to record action potentials at the same time as injecting an artificial, modifiable, ICaL (ICaL,D-C ). Progressively widening the ICaL,D-C window region produced EADs of various types, dependent on window width. EAD production was strongest upon moving the activation (vs. inactivation) side of the window. EADs were then induced by a different method: increasing ICaL,D-C amplitude and/or K+ channel-blockade (4-aminopyridine). Narrowing of the ICaL,D-C window by ∼10 mV abolished these EADs. Atrial ICaL window narrowing is worthy of further testing as a potential anti-atrial fibrillation drug mechanism. ABSTRACT: Atrial early-afterdepolarizations (EADs) may contribute to atrial fibrillation (AF), perhaps involving reactivation of L-type Ca2+ current (ICaL ) in its window region voltage range. The present study aimed (i) to validate the dynamic clamp technique for modifying the ICaL contribution to atrial action potential (AP) waveform; (ii) to investigate the effects of widening the window ICaL on EAD-propensity; and (iii) to test whether EADs from increased ICaL and AP duration are supressed by narrowing the window ICaL . ICaL and APs were recorded from rabbit and human atrial myocytes by whole-cell-patch clamp. During AP recording, ICaL was inhibited (3 µm nifedipine) and replaced by a dynamic clamp model current, ICaL,D-C (tuned to native ICaL characteristics), computed in real-time (every 50 µs) based on myocyte membrane potential. ICaL,D-C -injection restored the nifedipine-suppressed AP plateau. Widening the window ICaL,D-C , symmetrically by stepwise simultaneous equal shifts of half-voltages (V0.5 ) of ICaL,D-C activation (negatively) and inactivation (positively), generated EADs (single, multiple or preceding repolarization failure) in a window width-dependent manner, as well as AP alternans. A stronger EAD-generating effect resulted from independently shifting activation V0.5 (asymmetrical widening) than inactivation V0.5 ; for example, a 15 mV activation shift produced EADs in nine of 17 (53%) human atrial myocytes vs. 0 of 18 from inactivation shift (P < 0.05). In 11 rabbit atrial myocytes in which EADs were generated either by increasing the conductance of normal window width ICaL,D-C or subsequent 4-aminopyridine (2 mm), window ICaL,D-C narrowing (10 mV) abolished EADs of all types (P < 0.05). The present study validated the dynamic clamp for ICaL , which is novel in atrial cardiomyocytes, and showed that EADs of various types are generated by widening (particularly asymmetrically) the window ICaL , as well as abolished by narrowing it. Window ICaL narrowing is a potential therapeutic mechanism worth pursuing in the search for improved anti-AF drugs.

Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

AIMS: Action potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo. METHODS AND RESULTS: We developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans. CONCLUSION: Combined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

Novel non-invasive algorithm to identify the origins of re-entry and ectopic foci in the atria from 64-lead ECGs: A computational study.

Atrial tachy-arrhytmias, such as atrial fibrillation (AF), are characterised by irregular electrical activity in the atria, generally associated with erratic excitation underlain by re-entrant scroll waves, fibrillatory conduction of multiple wavelets or rapid focal activity. Epidemiological studies have shown an increase in AF prevalence in the developed world associated with an ageing society, highlighting the need for effective treatment options. Catheter ablation therapy, commonly used in the treatment of AF, requires spatial information on atrial electrical excitation. The standard 12-lead electrocardiogram (ECG) provides a method for non-invasive identification of the presence of arrhythmia, due to irregularity in the ECG signal associated with atrial activation compared to sinus rhythm, but has limitations in providing specific spatial information. There is therefore a pressing need to develop novel methods to identify and locate the origin of arrhythmic excitation. Invasive methods provide direct information on atrial activity, but may induce clinical complications. Non-invasive methods avoid such complications, but their development presents a greater challenge due to the non-direct nature of monitoring. Algorithms based on the ECG signals in multiple leads (e.g. a 64-lead vest) may provide a viable approach. In this study, we used a biophysically detailed model of the human atria and torso to investigate the correlation between the morphology of the ECG signals from a 64-lead vest and the location of the origin of rapid atrial excitation arising from rapid focal activity and/or re-entrant scroll waves. A focus-location algorithm was then constructed from this correlation. The algorithm had success rates of 93% and 76% for correctly identifying the origin of focal and re-entrant excitation with a spatial resolution of 40 mm, respectively. The general approach allows its application to any multi-lead ECG system. This represents a significant extension to our previously developed algorithms to predict the AF origins in association with focal activities.

In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis.

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.

A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions.

Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures to form dyads within which calcium-induced-calcium-release occurs. The organisation of these structures tightly controls intracellular calcium dynamics. In this study, we present a computational model of intracellular calcium cycling in three-dimensions (3-D), which incorporates high resolution reconstructions of these key regulatory structures, attained through imaging of tissue taken from the sheep left ventricle using serial block face scanning electron microscopy. An approach was developed to model the sarcoplasmic reticulum structure at the whole-cell scale, by reducing its full 3-D structure to a 3-D network of one-dimensional strands. The model reproduces intracellular calcium dynamics during control pacing and reveals the high-resolution 3-D spatial structure of calcium gradients and intracellular fluxes in both the cytoplasm and sarcoplasmic reticulum. We also demonstrated the capability of the model to reproduce potentially pro-arrhythmic dynamics under perturbed conditions, pertaining to calcium-transient alternans and spontaneous release events. Comparison with idealised cell models emphasised the importance of structure in determining calcium gradients and controlling the spatial dynamics associated with calcium-transient alternans, wherein the probabilistic nature of dyad activation and recruitment was constrained. The model was further used to highlight the criticality in calcium spark propagation in relation to inter-dyad distances. The model presented provides a powerful tool for future investigation of structure-function relationships underlying physiological and pathophysiological intracellular calcium handling phenomena at the whole-cell. The approach allows for the first time direct integration of high-resolution images of 3-D intracellular structures with models of calcium cycling, presenting the possibility to directly assess the functional impact of structural remodelling at the cellular scale.

Accuracy of Prehospital Identification of Stroke in a Large Stroke Belt Municipality.

OBJECTIVE: Strokes are a leading cause of morbidity and mortality in the United States, especially in the "stroke belt" of the southeast. Up to 65% of stroke patients access care by calling 9-1-1. The primary objective of this study is to measure the accuracy of emergency medical dispatchers (EMD) and paramedics, in the prehospital identification of stroke. METHODS: The study was based at Grady Emergency Medical Services, which is Atlanta, Georgia's public emergency medical services (EMS) provider. A retrospective analysis of all medically related 9-1-1 calls to Grady EMS classified as "stroke" between January 1, 2012, and December 31, 2012 was performed. A database was created using deterministic linkage between records from Grady EMS, Grady Hospital Emergency Department (ED), and the Grady Hospital Stroke Registry. Patients excluded were less than 18 years of age, had previous or concurrent head injuries, were transferred from another inpatient facility, and/or had incomplete patient records in any one of the three databases. Descriptive analysis, linear regression, and logistic multivariable regression were performed to discover the accuracy of stroke identification and contributory prehospital factors. RESULTS: A total of 548 patients were included: 475 were transported with EMS impression of stroke and 73 with an impression other than stroke. The median age was 59 years, 87.4% were black, and 52.6% were female. Paramedics adhered to all seven elements of the Grady EMS stroke protocol in 76.4% (n = 363) of suspected stroke cases. Sensitivity and positive predictive value for paramedic stroke identification was 76.2% and 49.3%, respectively, and for EMD, was 48.9% and 24%, respectively. Identification of hemorrhagic strokes had a relatively lower sensitivity. Paramedics were more likely to positively identify strokes when the Cincinnati Prehospital Stroke Scale (CPSS) screen was positive, or when classified by EMD as stroke. Paramedics were less likely to identify stroke in female patients. Paramedics' diagnostic accuracy was similar regardless of their adherence to the EMS stroke care protocol. CONCLUSIONS: EMD and EMS personnel in a large city in the Southeastern United States, with high stroke prevalence, had a relatively high sensitivity in identifying acute stroke patients. Paramedic accuracy was augmented by positive CPSS screening and by EMD recognition of stroke.

Atrial Heterogeneity Generates Re-entrant Substrate during Atrial Fibrillation and Anti-arrhythmic Drug Action: Mechanistic Insights from Canine Atrial Models.

Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF.

Novel Paramedic Programs Respond to Behavioral Health-related Calls.

A number of communities are turning to community paramedicine programs to help manage the crushing demand on EDs and EMS providers by patients with behavioral health (BH) concerns. In Modesto, CA, a pilot program provides extra training to paramedics to respond to BH-related calls, and a program in Atlanta pairs paramedics with mental health social workers to meet the needs of BH patients, many of whom repeatedly call 911 for help. Both programs curb the need for hospital and ED visits while linking patients with appropriate care more expeditiously. However, a shortage of psychiatric treatment facilities remains a barrier. Paramedics in the Modesto, CA, program undergo 140 hours of specialized training in how to handle BH related 911 calls safely and appropriately. Program developers note that most of these patients can be stabilized within 23 hours, nixing the need for a bed in an inpatient psychiatric facility. Developers say that the pilot program has saved more than $1 million and significantly reduced the time to treatment for BH patients. The Upstream Crisis Intervention program in Atlanta teams a paramedic with a mental health social worker to respond to BH related calls through a mental health unit that is dispatched through the 911 system. The mental health unit teams also check on BH patients when they are not in crisis to make sure they have their medicine and are on track with their plan of care; the teams will intervene if patients need assistance.

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.

Evolution and pharmacological modulation of the arrhythmogenic wave dynamics in canine pulmonary vein model.

AIMS: Atrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue. METHODS AND RESULTS: A previously developed biophysically detailed three-dimensional canine atrial model is applied. Effects of AF-induced electrical remodelling are introduced based on published experimental data, as changes of ion channel currents (ICaL, IK1, Ito, and IKur), the action potential (AP) and cell-to-cell coupling levels. Pharmacological effects are introduced by blocking specific ion channel currents. A combination of electrical heterogeneity (AP tissue gradients of 5-12 ms) and anisotropy (conduction velocities of 0.75-1.25 and 0.21-0.31 m/s along and transverse to atrial fibres) can results in the generation of wave breaks in the PV region. However, a long wavelength (171 mm) prevents the wave breaks from developing into re-entry. Electrical remodelling leads to decreases in the AP duration, conduction velocity and wavelength (to 49 mm), such that re-entry becomes sustained. Pharmacological effects on the tissue heterogeneity and vulnerability (to wave breaks and re-entry) are quantified to show that drugs that increase the wavelength and stop re-entry (IK1 and IKur blockers) can also increase the heterogeneity (AP gradients of 26-27 ms) and the likelihood of wave breaks. CONCLUSION: Biophysical modelling reveals large conduction block areas near the PVs, which are due to discontinuous fibre arrangement enhanced by electrical heterogeneity. Vulnerability to re-entry in such areas can be modulated by pharmacological interventions.

Effects of human atrial ionic remodelling by ß-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

AIMS: Atrial anti-arrhythmic effects of ß-adrenoceptor antagonists (ß-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic ß-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic ß-blocker therapy, i.e. independent of acute electrophysiological effects of ß-blockers, in an otherwise un-remodelled atrium, could suppress AF. METHODS AND RESULTS: Contemporarily, biophysically detailed human atrial cell and tissue models were used to investigate effects of the ß-blocker-based pharmacological remodelling. Chronic ß-blockade remodelling prolonged atrial cell APD and ERP. The incidence of small amplitude APD alternans in the CRN model was reduced. At the 1D tissue level, ß-blocker remodelling decreased the maximum pacing rate at which APs could be conducted. At the three-dimensional organ level, ß-blocker remodelling reduced the life span of re-entry scroll waves. CONCLUSION: This study improves our understanding of the electrophysiological mechanisms of AF suppression by chronic ß-blocker therapy. Atrial fibrillation suppression may involve a reduced propensity for maintenance of re-entrant excitation waves, as a consequence of increased APD and ERP.

How well do General EMS 911 dispatch protocols predict ED resource utilization for pediatric patients?

INTRODUCTION: The use of Emergency Medical Services (EMS) for low-acuity pediatric problems is well documented. Attempts have been made to curb potentially unnecessary transports, including using EMS dispatch protocols, shown to predict acuity and needs of adults. However, there are limited data about this in children. The primary objective of this study is to determine the pediatric emergency department (PED) resource utilization (surrogate of acuity level) for pediatric patients categorized as "low-acuity" by initial EMS protocols. METHODS: Records of all pediatric patients classified as "low acuity" and transported to a PED in winter and summer of 2010 were reviewed. Details of the PED visit were recorded. Patients were categorized and compared based on chief complaint group. Resource utilization was defined as requiring any prescription medications, labs, procedures, consults, admission or transfer. "Under-triage" was defined as a "low-acuity" EMS transport subsequently requiring emergent interventions. RESULTS: Of the 876 eligible cases, 801 were included; 392/801 had no resource utilization while 409 of 801 had resource utilization. Most (737/801) were discharged to home; however, 64/801 were admitted, including 1 of 801 requiring emergent intervention (under-triage rate 0.12%). Gastroenterology and trauma groups had a significant increase in resource utilization, while infectious disease and ear-nose-throat groups had decreased resource utilization. DISCUSSION: While this EMS system did not well predict overall resource utilization, it safely identified most low-acuity patients, with a low under-triage rate. This study identifies subgroups of patients that could be managed without emergent transport and can be used to further refine current protocols or establish secondary triage systems.

Caloric Restriction Rejuvenates Skeletal Muscle Growth in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major clinical problem, with limited treatments. HFpEF is characterized by a distinct, but poorly understood, skeletal muscle pathology, which could offer an alternative therapeutic target. In a rat model, we identified impaired myonuclear accretion as a mechanism for low myofiber growth in HFpEF following resistance exercise. Acute caloric restriction rescued skeletal muscle pathology in HFpEF, whereas cardiac therapies had no effect. Mechanisms regulating myonuclear accretion were dysregulated in patients with HFpEF. Overall, these findings may have widespread implications in HFpEF, indicating combined dietary with exercise interventions as a beneficial approach to overcome skeletal muscle pathology.