The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform

Michele Giugliano - One of the best experts on this subject based on the ideXlab platform.

  • Closed-Loop Methodologies for Cellular Electrophysiology
    Closed Loop Neuroscience, 2016
    Co-Authors: João Couto, Daniele Linaro, Rocco Pulizzi, Michele Giugliano
    Abstract:

    While the design of closed-loop experimental protocols in Cellular Electrophysiology dates back more than 60 years, recent developments promise to significantly advance the field. We review a selection of recent applications of closed-loop methods in neurobiology, focussing on the intraCellular and extraCellular access to Cellular excitability, employed to dissect the biophysical bases of information processing. We cover relevant methodologies targeting different levels of description, ranging from single ion channels to large ensembles of neurons, and extending across different time scales, ranging from milliseconds to longer intervals characteristic of the variability in the firing rate. We conclude by mentioning future perspectives and developments.

  • A reconfigurable visual-programming library for real-time closed-loop Cellular Electrophysiology.
    Frontiers in neuroinformatics, 2015
    Co-Authors: Istvan Biro, Michele Giugliano
    Abstract:

    Most of the software platforms for Cellular Electrophysiology are limited in terms of flexibility, hardware support, ease of use, or re-configuration and adaptation for non-expert users. Moreover, advanced experimental protocols requiring real-time closed-loop operation to investigate excitability, plasticity, dynamics, are largely inaccessible to users without moderate to substantial computer proficiency. Here we present an approach based on MATLAB/Simulink, exploiting the benefits of LEGO-like visual programming and configuration, combined to a small, but easily extendible library of functional software components. We provide and validate several examples, implementing conventional and more sophisticated experimental protocols such as dynamic-clamp or the combined use of intraCellular and extraCellular methods, involving closed-loop real-time control. The functionality of each of these examples is demonstrated with relevant experiments. These can be used as a starting point to create and support a larger variety of electrophysiological tools and methods, hopefully extending the range of default techniques and protocols currently employed in experimental labs across the world.

  • Command-line Cellular Electrophysiology for conventional and real-time closed-loop experiments.
    Journal of neuroscience methods, 2014
    Co-Authors: Daniele Linaro, João Couto, Michele Giugliano
    Abstract:

    Background: Current software tools for electrophysiological experiments are limited in flexibility and rarely offer adequate support for advanced techniques such as dynamic clamp and hybrid experiments, which are therefore limited to laboratories with a significant expertise in neuroinformatics. New method: We have developed LCG, a software suite based on a command-line interface (CLI) that allows performing both standard and advanced electrophysiological experiments. Stimulation protocols for classical voltage and current clamp experiments are defined by a concise and flexible meta description that allows representing complex waveforms as a piece-wise parametric decomposition of elementary sub-waveforms, abstracting the stimulation hardware. To perform complex experiments LCG provides a set of elementary building blocks that can be interconnected to yield a large variety of experimental paradigms. Results: We present various Cellular electrophysiological experiments in which LCG has been employed, ranging from the automated application of current clamp protocols for characterizing basic electrophysiological properties of neurons, to dynamic clamp, response clamp, and hybrid experiments. We finally show how the scripting capabilities behind a CLI are suited for integrating experimental trials into complex workflows, where actual experiment, online data analysis and computational modeling seamlessly integrate. Comparison with existing methods: We compare LCG with two open source toolboxes, RTXI and RELACS. Conclusions: We believe that LCG will greatly contribute to the standardization and reproducibility of both simple and complex experiments. Additionally, on the long run the increased efficiency due to a CLI will prove a great benefit for the experimental community. (C) 2014 Elsevier B.V. All rights reserved.

Blanca Rodriguez - One of the best experts on this subject based on the ideXlab platform.

  • experimentally calibrated population of models predicts and explains intersubject variability in cardiac Cellular Electrophysiology
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Oliver J Britton, Alfonso Buenoorovio, Karel Van Ammel, Rob Towart, David J Gallacher, Blanca Rodriguez
    Abstract:

    Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here, we describe a methodology to unravel the ionic determinants of intersubject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, because of their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje Electrophysiology, and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude, and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide.

  • Quantifying Importance of Repolarization Currents Underlying Physiological Variability in Rabbit Cellular Electrophysiology
    Biophysical Journal, 2012
    Co-Authors: Philip Gemmell, Blanca Rodriguez, Kevin Burrage, T. Alexander Quinn
    Abstract:

    Variability is observed in cardiac Electrophysiology measurements, but causes are unknown. We quantified the importance of repolarization currents underlying physiological action potential (AP) and calcium transient (CaT) variability using a rabbit ventricular AP model.Computer simulations using the Mahajan et al. model were conducted to determine effects on AP and CaT of simultaneous variation in peak conductance of IK1, IKr, IKs, Ito, ICa,L and INaK by up to ±30%. Combinations resulting in physiological response compared to original model output were determined for different percentages of variability at two pacing rates.Results demonstrate that 98 and 413 combinations result in physiological response at 2.5Hz, with less than 2.5% and 5.0% difference from control (Panel A). At both percentages, response is more sensitive to changes in peak conductance of Ito, ICa,L and INaK than in IKs, IKr and IK1 (Panel B). Considering measured physiological variability in experimental rabbit preparations increases combinations to 1,697. When data at 1Hz are also considered, this is reduced to 288.Relative importance of currents to variability in cardiac Electrophysiology can be quantified by combined computational and experimental investigations revealing conductance combinations resulting in physiological output.View Large Image | View Hi-Res Image | Download PowerPoint Slide

  • Systematic characterization of the ionic basis of rabbit Cellular Electrophysiology using two ventricular models.
    Progress in biophysics and molecular biology, 2011
    Co-Authors: Lucia Romero, B Carbonell, Beatriz Trenor, Blanca Rodriguez, Javier Saiz, Jose M. Ferrero
    Abstract:

    Abstract Several mathematical models of rabbit ventricular action potential (AP) have been proposed to investigate mechanisms of arrhythmias and excitation-contraction coupling. Our study aims at systematically characterizing how ionic current properties modulate the main Cellular biomarkers of arrhythmic risk using two widely-used rabbit ventricular models, and comparing simulation results using the two models with experimental data available for rabbit. A sensitivity analysis of AP properties, Ca 2+ and Na + dynamics, and their rate dependence to variations (±15% and ±30%) in the main transmembrane current conductances and kinetics was performed using the Shannon et al. (2004) and the Mahajan et al. (2008a,b) AP rabbit models. The effects of severe transmembrane current blocks (up to 100%) on steady-state AP and calcium transients, and AP duration (APD) restitution curves were also simulated using both models. Our simulations show that, in both virtual rabbit cardiomyocytes, APD is significantly modified by most repolarization currents, AP triangulation is regulated mostly by the inward rectifier K + current (I K1 ) whereas APD rate adaptation as well as [Na + ] i rate dependence is influenced by the Na + /K + pump current (I NaK ). In addition, steady-state [Ca 2+ ] i levels, APD restitution properties and [Ca 2+ ] i rate dependence are strongly dependent on I NaK , the L-Type Ca 2+ current (I CaL ) and the Na + /Ca 2+ exchanger current (I NaCa ), although the relative role of these currents is markedly model dependent. Furthermore, our results show that simulations using both models agree with many experimentally-reported electrophysiological characteristics. However, our study shows that the Shannon et al. model mimics rabbit Electrophysiology more accurately at normal pacing rates, whereas Mahajan et al. model behaves more appropriately at faster rates. Our results reinforce the usefulness of sensitivity analysis for further understanding of Cellular Electrophysiology and validation of cardiac AP models.

  • Impact of ionic current variability on human ventricular Cellular Electrophysiology.
    American journal of physiology. Heart and circulatory physiology, 2009
    Co-Authors: Lucia Romero, Esther Pueyo, Martin Fink, Blanca Rodriguez
    Abstract:

    Abnormalities in repolarization and its rate dependence are known to be related to increased proarrhythmic risk. A number of repolarization-related electrophysiological properties are commonly used...

Istvan Biro - One of the best experts on this subject based on the ideXlab platform.

  • A reconfigurable visual-programming library for real-time closed-loop Cellular Electrophysiology.
    Frontiers in neuroinformatics, 2015
    Co-Authors: Istvan Biro, Michele Giugliano
    Abstract:

    Most of the software platforms for Cellular Electrophysiology are limited in terms of flexibility, hardware support, ease of use, or re-configuration and adaptation for non-expert users. Moreover, advanced experimental protocols requiring real-time closed-loop operation to investigate excitability, plasticity, dynamics, are largely inaccessible to users without moderate to substantial computer proficiency. Here we present an approach based on MATLAB/Simulink, exploiting the benefits of LEGO-like visual programming and configuration, combined to a small, but easily extendible library of functional software components. We provide and validate several examples, implementing conventional and more sophisticated experimental protocols such as dynamic-clamp or the combined use of intraCellular and extraCellular methods, involving closed-loop real-time control. The functionality of each of these examples is demonstrated with relevant experiments. These can be used as a starting point to create and support a larger variety of electrophysiological tools and methods, hopefully extending the range of default techniques and protocols currently employed in experimental labs across the world.

Daniele Linaro - One of the best experts on this subject based on the ideXlab platform.

  • Closed-Loop Methodologies for Cellular Electrophysiology
    Closed Loop Neuroscience, 2016
    Co-Authors: João Couto, Daniele Linaro, Rocco Pulizzi, Michele Giugliano
    Abstract:

    While the design of closed-loop experimental protocols in Cellular Electrophysiology dates back more than 60 years, recent developments promise to significantly advance the field. We review a selection of recent applications of closed-loop methods in neurobiology, focussing on the intraCellular and extraCellular access to Cellular excitability, employed to dissect the biophysical bases of information processing. We cover relevant methodologies targeting different levels of description, ranging from single ion channels to large ensembles of neurons, and extending across different time scales, ranging from milliseconds to longer intervals characteristic of the variability in the firing rate. We conclude by mentioning future perspectives and developments.

  • Command-line Cellular Electrophysiology for conventional and real-time closed-loop experiments.
    Journal of neuroscience methods, 2014
    Co-Authors: Daniele Linaro, João Couto, Michele Giugliano
    Abstract:

    Background: Current software tools for electrophysiological experiments are limited in flexibility and rarely offer adequate support for advanced techniques such as dynamic clamp and hybrid experiments, which are therefore limited to laboratories with a significant expertise in neuroinformatics. New method: We have developed LCG, a software suite based on a command-line interface (CLI) that allows performing both standard and advanced electrophysiological experiments. Stimulation protocols for classical voltage and current clamp experiments are defined by a concise and flexible meta description that allows representing complex waveforms as a piece-wise parametric decomposition of elementary sub-waveforms, abstracting the stimulation hardware. To perform complex experiments LCG provides a set of elementary building blocks that can be interconnected to yield a large variety of experimental paradigms. Results: We present various Cellular electrophysiological experiments in which LCG has been employed, ranging from the automated application of current clamp protocols for characterizing basic electrophysiological properties of neurons, to dynamic clamp, response clamp, and hybrid experiments. We finally show how the scripting capabilities behind a CLI are suited for integrating experimental trials into complex workflows, where actual experiment, online data analysis and computational modeling seamlessly integrate. Comparison with existing methods: We compare LCG with two open source toolboxes, RTXI and RELACS. Conclusions: We believe that LCG will greatly contribute to the standardization and reproducibility of both simple and complex experiments. Additionally, on the long run the increased efficiency due to a CLI will prove a great benefit for the experimental community. (C) 2014 Elsevier B.V. All rights reserved.

Stanley Nattel - One of the best experts on this subject based on the ideXlab platform.

  • Computational models of atrial Cellular Electrophysiology and calcium handling, and their role in atrial fibrillation.
    The Journal of physiology, 2015
    Co-Authors: Jordi Heijman, Niels Voigt, Stanley Nattel, Pegah Erfanian Abdoust, Dobromir Dobrev
    Abstract:

    The complexity of the heart makes an intuitive understanding of the relative contribution of ion channels, transporters and signalling pathways to cardiac Electrophysiology challenging. Computational modelling of cardiac Cellular Electrophysiology has proven useful to integrate experimental findings, extrapolate results obtained in expression systems or animal models to other systems, test quantitatively ideas based on experimental data and provide novel hypotheses that are experimentally testable. While the bulk of computational modelling has traditionally been directed towards ventricular bioelectricity, increasing recognition of the clinical importance of atrial arrhythmias, particularly atrial fibrillation, has led to widespread efforts to apply computational approaches to understanding atrial electrical function. The increasing availability of detailed, atrial-specific experimental data has stimulated the development of novel computational models of atrial-Cellular Electrophysiology and Ca(2+) handling. To date, more than 300 studies have employed mathematical simulations to enhance our understanding of atrial Electrophysiology, arrhythmogenesis and therapeutic responses. Future modelling studies are likely to move beyond current whole-cell models by incorporating new data on subCellular architecture, macromolecular protein complexes, and localized ion-channel regulation by signalling pathways. At the same time, more integrative multiCellular models that take into account regional electrophysiological and Ca(2+) handling properties, mechano-electrical feedback and/or autonomic regulation will be needed to investigate the mechanisms governing atrial arrhythmias. A combined experimental and computational approach is expected to provide the more comprehensive understanding of atrial arrhythmogenesis that is required to develop improved diagnostic and therapeutic options. Here, we review this rapidly expanding area, with a particular focus on Ca(2+) handling, and provide ideas about potential future directions.

  • arrhythmogenic left atrial Cellular Electrophysiology in a murine genetic long qt syndrome model
    Cardiovascular Research, 2011
    Co-Authors: Marc D Lemoine, Stanley Nattel, Larissa Fabritz, Denis Chartier, James Elber Duverger, Patrice Naud, Philippe Comtois, Paulus Kirchhof
    Abstract:

    Aims Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial Cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte Electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes). Methods and results Peak and late Na+ current ( I NaP and I NaL) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multiCellular LA preparations with floating microelectrodes. I NaL was increased by 110% in LA cardiomyocytes of ΔKPQ mice, whereas I NaP was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD90 at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P < 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs. 1/10 WT (10%) atria ( P < 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I NaL (50% inhibitory concentration: 12.5 vs. 151.8 µM for I NaP) in ΔKPQ myocytes. At 10 µM, ranolazine shortened APD (e.g. APD90 at 0.5 Hz to 122 ± 4 ms, P = 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P < 0.05). Conclusion This study implicates increased I NaL in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications.

  • Cellular Electrophysiology and the Substrate for Atrial Fibrillation
    Atrial Fibrillation, 2008
    Co-Authors: Joachim R. Ehrlich, Pierre Coutu, Yung-hsin Yeh, Stanley Nattel
    Abstract:

    This chapter focuses on basic Cellular atrial Electrophysiology and tries to pinpoint the consequences of cardiac conditions that play a role in creating a substrate for atrial fibrillation. It touches on a series of Cellular alterations that contribute to substrate and trigger formation. These include changes in ionic currents, cell—cell connections via connexins, calcium handling alterations, and genetic predispositions.

  • Cellular Electrophysiology of canine pulmonary vein cardiomyocytes action potential and ionic current properties
    The Journal of Physiology, 2003
    Co-Authors: Joachim R. Ehrlich, Liming Zhang, Denis Chartier, Peter Melnyk, Stefan H Hohnloser, Stanley Nattel
    Abstract:

    Pulmonary vein (PV) cardiomyocytes play an important role in atrial fibrillation; however, little is known about their specific Cellular electrophysiological properties. We applied standard microelectrode recording and whole-cell patch-clamp to evaluate action potentials and ionic currents in canine PVs and left atrium (LA) free wall. Resting membrane potential (RMP) averaged −66 ± 1 mV in PVs and −74 ± 1 mV in LA (P < 0.0001) and action potential amplitude averaged 76 ± 2 mV in PVs vs. 95 ± 2 mV in LA (P < 0.0001). PVs had smaller maximum phase 0 upstroke velocity (Vmax: 98 ± 9 vs. 259 ± 16 V s−1, P < 0.0001) and action potential duration (APD): e.g. at 2 Hz, APD to 90 % repolarization in PVs was 84 % of LA (P < 0.05). Na+ current density under voltage-clamp conditions was similar in PV and LA, suggesting that smaller Vmax in PVs was due to reduced RMP. Inward rectifier current density in the PV cardiomyocytes was ˜58 % that in the LA, potentially accounting for the less negative RMP in PVs. Slow and rapid delayed rectifier currents were greater in the PV (by ˜60 and ˜50 %, respectively), whereas transient outward K+ current and L-type Ca2+ current were significantly smaller (by ˜25 and ˜30 %, respectively). Na+-Ca2+-exchange (NCX) current and T-type Ca2+ current were not significantly different. In conclusion, PV cardiomyocytes have a discrete distribution of transmembrane ion currents associated with specific action potential properties, with potential implications for understanding PV electrical activity in cardiac arrhythmias.

  • Cellular Electrophysiology of atrial fibrillation
    Cardiovascular research, 2002
    Co-Authors: Ralph F. Bosch, Stanley Nattel
    Abstract:

    Time for primary review 23 days. Atrial fibrillation (AF) is presently the most common cardiac arrhythmia in clinical practice. Its treatment is inadequate. Maintenance of normal sinus rhythm (SR) is obviously the optimal approach, but is difficult to achieve without drugs that have the potential to cause ventricular proarrhythmia and increase mortality. Non-pharmacological therapy is attractive, but to date has not reached the same level of efficacy as in the treatment of arrhythmias other than AF. In order to improve therapeutic approaches, it is important to understand the detailed pathophysiology of the arrhythmia. A key component to the pathophysiology of any cardiac arrhythmia is the Cellular milieu in which it occurs. Changes in ion transport processes, including pumps, channels and exchangers, are central to alterations in action potential properties that govern the occurrence of arrhythmias like AF. Action potential duration (APD) determines the refractory period and is therefore a key determinant of the likelihood of reentry. Maximum Na+-current ( I Na) governs phase 0 upstroke velocity, determining conduction velocity (CV) and contributing to the likelihood of reentry. Delayed and early afterdepolarizations produce abnormal activity that can in themselves produce tachyarrhythmias and can trigger reentrant arrhythmia. This paper reviews these aspects of the Cellular Electrophysiology of AF, attempting to summarize what is known, what remains to be explored and what this information can teach us about why AF occurs and how to treat it. The identification of the molecular structure of many ion channels involved in cardiac excitability and their functional correlation with native ionic currents have made it possible to study the effects of pathophysiological conditions, like AF, at different levels from genes to ionic currents. The different steps underlying the expression of an ion channel are depicted in Fig. 1 and have recently been reviewed by Roden and … * Corresponding author. Tel.: +49-7071-298-3196; fax: +49-7071-294-121 ralph.bosch{at}uni-tuebingen.de