Reconstruction of atrial ectopic focal and Re-entrant excitations from body surface potentials. Insights from 3D virtual human atria and torso

Non-invasive electrocardiographic imaging has been seen as a painless and economic method to map the electrical functions of the heart. However, it is still a great challenge to obtain accurate reconstruction of cardiac electrical activity from body surface potentials (BSP) due to the ill-posed behaviour of the cardiac inverse-problem. Though some advances have been made in solving the inverse-problem, few studies have been conducted for the atria, which have dramatic differences to the ventricles in their anatomical structures and electrophysiological properties. It is unclear either how the spatial resolution of electrodes on the BSP and rapid excitation rates of atrial activation during atrial fibrillation affect the accuracy of the inverse-problem. In this study, we used a biophysically detailed model of the human atria and torso to investigate effects of multi-lead ECG on the accuracy of reconstructed atrial excitation pattern on the epicardiac surface during the time courses of atrial fibrillation induced by electrical remodelling. It was shown that the solution of the atrial inverse-problem was dependent on the spatial resolution of electrodes on the body surface. The solution was also influenced by the morphology of the AP, rate and types of atrial excitation as well as the implantation of variant orders of the Tikhonov regularization method

The effect of bioenergetic impairment of cytosolic processes in spatio-temporal Ca²⁺ dynamics in a three-dimensional cardiomyocyte model

The heart consumes large amounts of energy with each beat. Mitochondria are the source of over 95% of this energy in the form of ATP and rely on increased Ca²⁺ uptake to stimulate production in times of increased work. Ca²⁺ uptake into the mitochondria primarily occurs within microdomains. Structural remodeling associated with heart failure may disrupt these microdomains leading to impaired mitochondrial Ca²⁺ uptake and energetic impairment. To investigate the effect of structural changes on single cell behavior, a model describing mitochondrial dynamics and energetics production is modified and incorporated into a recently developed three-dimensional model of spatio-temporal calcium handling, which preserves microdomain structure and incorporates stochastic processes in Ca²⁺ handling protein kinetics. Modifications to the mitochondria model included a reformulation of mitochondrial Ca²⁺ uniporter uptake, making it suitable for concentrations in microdomains. With this model we demonstrate the importance of an ordered structure within the cell for normal function. Changes in the arrangement of mitochondria can have a pronounced effect on intracellular Ca²⁺ dynamics through their energetic regulation of SERCA, leading to spatially heterogeneous sarcoplasmic reticulum uptake and loading

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

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

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

Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

Introduction: The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors) sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers. Methods: 3D atrial models integrated human atrial geometry, rule-based fiber orientation, region-specific electrophysiology, and AF-induced ionic remodeling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F) coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0–healthy tissue, 5–dense fibrosis) were identified based on LGE MRI intensity and modeled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2) fibrosis was considered for comparison. Results: In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV). In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors stabilized in fibrotic regions. The rotors propagated slowly around the border zones of patchy fibrosis (levels 3–4), failing to spread into inner areas of dense fibrosis. Conclusion: Rotors stabilize in the border zones of patchy fibrosis in 3D atria, where slow conduction enable the development of circuits within relatively small regions. Our results can provide a mechanistic explanation for the clinical efficacy of ablation around fibrotic regions

Computational Modelling of Cardiac Electrophysiological Changes in Malarial Fever

Cardiac function is impaired in severe malarial fever, and ECGs show changes associated with repolarization. These could contribute to mortality via ventricular arrhythmia. The cardiac effects could be due to the malarial parasite load in the heart, specific cardio-toxic effects of the parasite or cardio-toxic effects of antimalarial agents. We construct a simple 1-dimensional electrophysiological model for the physico-chemical changes clinically observed during malarial fever: with temperature, pH and [ionic]plasma changes. The model can quantitatively reproduce the tachycardia and QTc prolongation seen in the adult, and shortening seen in the child during malarial fever

Large-scale latitudinal and vertical distributions of NMHCs and selected halocarbons in the troposphere over the Pacific Ocean during the March-April 1999 Pacific Exploratory Mission (PEM-Tropics B)

Nonmethane hydrocarbons (NMHCs) and selected halocarbons were measured in whole air samples collected over the remote Pacific Ocean during NASA's Global Tropospheric Experiment (GTE) Pacific Exploratory Mission-Tropics B (PEM-Tropics B) in March and early April 1999. The large-scale spatial distributions of NMHCs and C2Cl4 reveal a much more pronounced north-south interhemispheric gradient, with higher concentrations in the north and lower levels in the south, than for the late August to early October 1996 PEM-Tropics A experiment. Strong continental outflow and winter-long accumulation of pollutants led to seasonally high Northern Hemisphere trace gas levels during PEM-Tropics B. Observations of enhanced levels of Halon 1211 (from developing Asian nations such as the PRC) and CH3Cl (from SE Asian biomass burning) support a significant southern Asian influence at altitudes above 1 km and north of 10° N. By contrast, at low altitude over the North Pacific the dominance of urban/industrial tracers, combined with low levels of Halon 1211 and CH3Cl, indicate a greater influence from developed nations such as Japan, Europe, and North America. Penetration of air exhibiting aged northern hemisphere characteristics was frequently observed at low altitudes over the equatorial central and western Pacific south to ∼5° S. The relative lack of southern hemisphere biomass burning sources and the westerly position of the South Pacific convergence zone contributed to significantly lower PEM-Tropics B mixing ratios of the NMHCs and CH3Cl south of 10° S compared to PEM-Tropics A. Therefore the trace gas composition of the South Pacific troposphere was considerably more representative of minimally polluted tropospheric conditions during PEM-Tropics B. Copyright 2001 by the American Geophysical Union

Distribution and growth rates of immature hawksbill turtles Eretmochelys imbricata in Fernando de Noronha, Brazil

This is the final version. Available on open access from Inter-Research via the DOI in this recordKnowledge of life history parameters is essential for the effective management of species of conservation concern. For migratory marine vertebrates such as hawksbill sea turtles Eretmochelys imbricata, feeding aggregations are important developmental habitats, allowing the study of population dynamics. Here, we used data from a 31 yr mark-recapture study of juvenile hawksbill sea turtles in the Fernando de Noronha Archipelago, Brazil, to estimate key demographic parameters. Turtles recruit to the neritic habitat at similar sizes to those of other Atlantic hawksbill aggregations. The curved carapace length (CCL) at the first capture ranged from 28 to 84 cm (mean ± SD: 44.6 ± 9.8 cm). Median minimum residence time of turtles captured at least twice was 3.2 yr, whilst long-term minimum residence of up to 14 yr was also observed, with turtles showing site fidelity within the archipelago. The mean size of turtles captured was constant throughout time. Turtles grew on average 3.4 ± 2.2 cm yr-1, with a monotonic expected growth rate function generally decreasing with increasing size. At these rates, hawksbill turtles in Fernando de Noronha would need to spend ca. 14-18 yr to reach minimum adult breeding size (~74 cm CCL). This mark-recapture study has been essential to understanding the ecology and demographic parameters of this regional hawksbill turtle neritic foraging ground.National Council for Scientific and Technological Development (CNPq), Brazi