A computational human atrial myofibroblast electrophysiological model
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ABSTRACT:
SUBMITTER: 
David Nickerson
PROVIDER: 785 | Physiome Model Repository |
REPOSITORIES: PMR
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Project description:Biophysically detailed mathematical models of cardiac electrophysiology provide an alternative to experimental approaches for investigating possible ionic mechanisms underlying the genesis of electrical action potentials and their propagation through the heart. The aim of this study was to develop a biophysically detailed mathematical model of the action potentials of mouse atrial myocytes, a popular experimental model for elucidating molecular and cellular mechanisms of arrhythmogenesis. Based on experimental data from isolated mouse atrial cardiomyocytes, a set of mathematical equations for describing the biophysical properties of membrane ion channel currents, intracellular Ca2+ handling, and Ca2+-calmodulin activated protein kinase II and β-adrenergic signaling pathways were developed. Wherever possible, membrane ion channel currents were modeled using Markov chain formalisms, allowing detailed representation of channel kinetics. The model also considered heterogeneous electrophysiological properties between the left and the right atrial cardiomyocytes. The developed model was validated by its ability to reproduce the characteristics of action potentials and Ca2+ transients, matching quantitatively to experimental data. Using the model, the functional roles of four K+ channel currents in atrial action potential were evaluated by channel block simulations, results of which were quantitatively in agreement with existent experimental data. To conclude, this newly developed model of mouse atrial cardiomyocytes provides a powerful tool for investigating possible ion channel mechanisms of atrial electrical activity at the cellular level and can be further used to investigate mechanisms underlying atrial arrhythmogenesis.
| S-EPMC7425199 | biostudies-literature
Project description:IntroductionAdvancing age is a known risk factor for developing atrial fibrillation (AF), yet it is unknown which electrophysiological changes contribute to this increased susceptibility. The goal of this study is to investigate conduction disturbances and unipolar voltages (UV) related to aging.MethodsWe included 216 patients (182 male, age: 36-83 years) without a history of AF undergoing elective coronary artery bypass surgery. Five seconds of sinus rhythm were recorded intraoperatively at the right atrium (RA), Bachmann's bundle (BB), the left atrium and the pulmonary vein area (PVA). Conduction delay (CD), -block (CB), -velocity (CV), length of longest CB lines and UV were assessed in all regions.ResultsWith aging, increasing conduction disturbances were found, particularly at RA and BB (RA: longest CB line rs = .158, p = .021; BB: CB prevalence rs = .206, p = .003; CV rs = -.239, p < .0005). Prevalence of low UV areas (UV <5th percentile) increased with aging at the BB and PVA (BB: rs = .237, p < .0005 and PVA: rs = .228, p = .001).ConclusionsAging is accompanied by an increase in conduction disturbances during sinus rhythm and a higher prevalence of low UV areas, particularly at BB and in the RA. These electrophysiological alterations could in part explain the increasing susceptibility to AF development associated with aging.
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Project description:Background: Cardiac pacemaking remains an unsolved matter from many perspectives. Extensive experimental and computational studies have been performed to describe the sinoatrial physiology across different scales, from the molecular to clinical levels. Nevertheless, the mechanism by which a heartbeat is generated inside the sinoatrial node and propagated to the working myocardium is not fully understood at present. This work aims to provide quantitative information about this fascinating phenomenon, especially regarding the contributions of cellular heterogeneity and fibroblasts to sinoatrial node automaticity and atrial driving. Methods: We developed a bidimensional computational model of the human right atrial tissue, including the sinoatrial node. State-of-the-art knowledge of the anatomical and physiological aspects was adopted during the design of the baseline tissue model. The novelty of this study is the consideration of cellular heterogeneity and fibroblasts inside the sinoatrial node for investigating the manner by which they tune the robustness of stimulus formation and conduction under different conditions (baseline, ionic current blocks, autonomic modulation, and external high-frequency pacing). Results: The simulations show that both heterogeneity and fibroblasts significantly increase the safety factor for conduction by more than 10% in almost all the conditions tested and shorten the sinus node recovery time after overdrive suppression by up to 60%. In the human model, especially under challenging conditions, the fibroblasts help the heterogeneous myocytes to synchronise their rate (e.g. -82% in σCL under 25 nM of acetylcholine administration) and capture the atrium (with 25% L-type calcium current block). However, the anatomical and gap junctional coupling aspects remain the most important model parameters that allow effective atrial excitations. Conclusion: Despite the limitations to the proposed model, this work suggests a quantitative explanation to the astonishing overall heterogeneity shown by the sinoatrial node.
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Project description:Improvements in quantitative measurements of human physical activity are proving extraordinarily useful for studying the underlying musculoskeletal system. Dynamic models of human movement support clinical efforts to analyze, rehabilitate injuries. They are also used in biomechanics to understand and diagnose motor pathologies, find new motor strategies that decrease the risk of injury, and predict potential problems from a particular procedure. In addition, they provide valuable constraints for understanding neural circuits. This paper describes a physics-based movement analysis method for analyzing and simulating bipedal humanoid movements. The model includes the major body segments and joints to report human movements' energetic components. Its 48 degrees of freedom strike a balance between very detailed models that include muscle models and straightforward two-dimensional models. It has sufficient accuracy to analyze and synthesize movements captured in real-time interactive applications, such as psychophysics experiments using virtual reality or human-in-the-loop teleoperation of a simulated robotic system. The dynamic model is fast and robust while still providing results sufficiently accurate to be used to animate a humanoid character. It can also estimate internal joint forces used during a movement to create effort-contingent stimuli and support controlled experiments to measure the dynamics generating human behaviors systematically. The paper describes the innovative features that allow the model to integrate its dynamic equations accurately and illustrates its performance and accuracy with demonstrations. The model has a two-foot stance ability, capable of generating results comparable with an experiment done with subjects, and illustrates the uncontrolled manifold concept. Additionally, the model's facility to capture large energetic databases opens new possibilities for theorizing as to human movement function. The model is freely available.
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Project description:The present study aims to connect the psychophysical research on the human visual perception of flicker with the neurophysiological research on steady-state visual evoked potentials (SSVEPs) in the context of their application needs and current technological developments. In four experiments, we investigated whether a temporal contrast sensitivity model could be established based on the electrophysiological responses to repetitive visual stimulation and, if so, how this model compares to the psychophysical models of flicker visibility. We used data from 62 observers viewing periodic flicker at a range of frequencies and modulation depths sampled around the perceptual visibility thresholds. The resulting temporal contrast sensitivity curve (TCSC) was similar in shape to its psychophysical counterpart, confirming that the human visual system is most sensitive to repetitive visual stimulation at frequencies between 10 and 20 Hz. The electrophysiological TCSC, however, was below the psychophysical TCSC measured in our experiments for lower frequencies (1-50 Hz), crossed it when the frequency was 50 Hz, and stayed above while decreasing at a slower rate for frequencies in the gamma range (40-60 Hz). This finding provides evidence that SSVEPs could be measured even without the conscious perception of flicker, particularly at frequencies above 50 Hz. The cortical and perceptual mechanisms that apply at higher temporal frequencies, however, do not seem to directly translate to lower frequencies. The presence of harmonics, which show better response for many frequencies, suggests non-linear processing in the visual system. These findings are important for the potential applications of SSVEPs in studying, assisting, or augmenting human cognitive and sensorimotor functions.
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Project description:To overcome limitations of minimally invasive surgical ablation as a standalone procedure in eliminating atrial fibrillation (AF), hybrid approaches incorporating adjunctive endovascular catheter ablation have been proposed in recent years. The endovascular component targets residual conduction gaps and identifies additional electrophysiological targets with the goal of minimizing recurrent atrial arrhythmia. We performed a systematic review of published studies of hybrid AF ablation, analyzing 432 pooled patients (19% paroxysmal, 29% persistent, 52% long-standing persistent) treated using three different approaches: A. bilateral thoracoscopy with bipolar radiofrequency (RF) clamp-based approach; B. right thoracoscopic suction monopolar RF catheter-based approach; and C. subxiphoid posterior pericardioscopic ("convergent") approach. Freedom from recurrence off antiarrhythmic medications at 12 months was seen in 88.1% [133/151] for A, 73.4% [47/64] for B, and 59.3% [80/135] for C, with no significant difference between paroxysmal (76.9%) and persistent/long-standing persistent AF (73.4%). Death and major surgical complications were reported in 8.5% with A, 0% with B and 8.6% with C. A critical appraisal of hybrid ablation is presented, drawing from experiences and insights published over the years on catheter ablation of AF, with a discussion of the rationale underlying hybrid ablation, its strengths and limitations, where it may have a unique role in clinical management of patients with AF, which questions remain unanswered and areas for further investigation.
| S-EPMC5135186 | biostudies-literature
Project description:The motility of the stomach is coordinated by an electrical activity termed "slow waves", and slow-wave dysrhythmias contribute to motility disorders. One major method for clinically evaluating gastric dysrhythmias has been electrogastrography (EGG); however, the clinical utility of EGG is limited partly due to the uncertainty regarding its electrophysiological basis. In this study, a multiscale model of gastric slow waves was generated from a biophysically based continuum description of cellular electrical events, coupled with a subject-specific human stomach model and high-resolution electrical mapping data. The model was then applied using a forward-modeling approach, within an anatomical torso model, to define how slow wave activity summates to generate the EGG potentials. The simulated EGG potentials were shown to be spatially varying in amplitude (0.27-0.33 mV) and duration (9.2-15.3 s), and the sources of this variance were quantified with respect to the activation timings of the underlying slow wave activity. This model constitutes an improved theory of the electrophysiological basis of the EGG, and offers a framework for optimizing the placement of EGG electrodes, and for interpreting the EGG changes occurring in disease states.
| S-EPMC2965998 | biostudies-literature
Project description:Nearly 1% of babies are born with congenital heart disease (CHD) – many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients (n=117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes (DEGs) revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower IKr expression in younger patients, a finding potentially tied to an increased amplitude of IKs that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development.
2024-11-01 | GSE276839 | GEO
Project description:Atrial arrhythmias, and specifically atrial fibrillation (AF), induce rapid and irregular activation patterns that appear on the torso surface as abnormal P-waves in electrocardiograms and body surface potential maps (BSPM). In recent years both P-waves and the BSPM have been used to identify the mechanisms underlying AF, such as localizing ectopic foci or high-frequency rotors. However, the relationship between the activation of the different areas of the atria and the characteristics of the BSPM and P-wave signals are still far from being completely understood. In this work we developed a multi-scale framework, which combines a highly-detailed 3D atrial model and a torso model to study the relationship between atrial activation and surface signals in sinus rhythm. Using this multi scale model, it was revealed that the best places for recording P-waves are the frontal upper right and the frontal and rear left quadrants of the torso. Our results also suggest that only nine regions (of the twenty-one structures in which the atrial surface was divided) make a significant contribution to the BSPM and determine the main P-wave characteristics.
| S-EPMC4629897 | biostudies-literature
Project description:Our previous study implied a correlation of inhibitors of differentiation-1 (Id-1) to cervical cancer development. However, how Id-1 contributes to cervical carcinogenesis is unknown. In the present study, we investigated the role of Id-1 in transforming cervical cells with an in vitro transformation model. The human papillomavirus (HPV) immortalized cervical epithelial cells (H8) were successfully transformed by exposure to the carcinogen N-nitrosopyrrolidine (NPYR). The results showed that both Id-1 RNA and protein expression were significantly increased in transformed H8 cells, suggesting a possible role of Id-1 in cervical cell transformation. Ectopic expression of Id-1 in H8 cells potentiated NPYR-induced cell transformation. In contrast, silencing of Id-1 suppressed NPYR-induced H8 cell transformation. A cDNA microarray assay was performed, which identified suggested potential cell signaling pathways for NPYR-induced H8 cell transformation. The results suggest that Id-1 plays an oncogenic role in the cervix, which sheds light on cervical cancer development and implies potential target for cervical cancer prevention and therapy.
2013-05-11 | GSE46842 | GEO