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Bioelectrical-biomechanical interactions in cardiac tissue and ephaptic conduction: two challenging aspects of cardiac electrophysiology

Applicant Kucera Jan Pavel
Number 156738
Funding scheme Project funding (Div. I-III)
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.10.2014 - 31.03.2018
Approved amount 550'000.00
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All Disciplines (3)

Discipline
Cardiovascular Research
Other disciplines of Engineering Sciences
Biophysics

Keywords (14)

computer modeling; ion currents; cardiac cell cultures; cardiac conduction; conduction velocity; ephaptic conduction; action potential; mechano-electrical coupling; conduction block; conduction stability; cardiac arrhythmias; stretchable microelectrode arrays; gap junctions; sodium channels

Lay Summary (French)

Lead
L’excitation électrique coordonnée et rythmique du cœur est essentielle pour assurer sa fonction mécanique qui est de faire circuler le sang dans l’organisme. Les arythmies cardiaques (troubles du rythme) sont étroitement associées aux maladies du cœur. Elles peuvent précipiter une insuffisance cardiaque, entraîner un accident vasculaire cérébral et causer un arrêt cardiaque. Malgré les progrès de la recherche visant à comprendre les mécanismes des arythmies, différents aspects nécessitent encore des connaissances plus approfondies. Nous en aborderons deux en utilisant des méthodes in vitro étayées par des simulations sur ordinateur basées sur des modèles mathématiques.
Lay summary

Contenu et objectif des travaux de recherche

Le premier projet a pour but d’étudier les effets d’une déformation du tissu cardiaque sur son activité électrique. Nous développerons des matrices de microélectrodes étirables sur lesquelles nous ferons croître des cultures de cellules cardiaques (un modèle in vitro du tissu cardiaque), ce qui permettra d’appliquer des déformations contrôlées à ces cultures et d’y enregistrer simultanément la propagation de l’excitation électrique (potentiel d’action). Cette approche nous permettra notamment de différencier les effets causés par une déformation parallèle à la direction de la propagation du potentiel d’action de ceux induits par une déformation dans un axe perpendiculaire.
Le deuxième projet vise à comprendre plus en détail les mécanismes fondamentaux de la propagation de l’excitation cardiaque. Le potentiel d’action se propage d’une cellule à la suivante grâce à des courants électriques passant à travers des canaux intercellulaires. Cependant, une autre théorie encore controversée propose que le courant produit par les canaux à ions sodium génère un potentiel extracellulaire substantiel dans les fentes étroites situées entre les cellules, ce qui contribuerait à activer ces canaux dans la cellule suivante. Avec des lignées cellulaires exprimant des canaux ioniques cardiaques, nous effectuerons des expériences qui permettront soit de confirmer, soit de réfuter cette hypothèse.

Contexte scientifique et social du projet de recherche

Nous estimons que les connaissances qui découleront de ces études seront profitables à l’avenir pour le développement de stratégies thérapeutiques et préventives plus efficaces des arythmies cardiaques qui représentent un facteur de morbidité et de mortalité important dans le cadre des maladies du cœur.

Direct link to Lay Summary Last update: 25.09.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Uniaxial strain of cultured mouse and rat cardiomyocyte strands slows conduction more when its axis is parallel to impulse propagation than when it is perpendicular
Buccarello A., Azzarito M., Michoud F., Lacour S. P., Kucera J. P. (2018), Uniaxial strain of cultured mouse and rat cardiomyocyte strands slows conduction more when its axis is parallel to impulse propagation than when it is perpendicular, in Acta Physiologica, 223(1), e13026-e13026.
Distribution of cardiac sodium channels in clusters potentiates ephaptic interactions in the intercalated disc
Hichri Echrak, Abriel Hugues, Kucera Jan P. (2018), Distribution of cardiac sodium channels in clusters potentiates ephaptic interactions in the intercalated disc, in The Journal of Physiology, 596(4), 563-589.
Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis
Kucera Jan P., Rohr Stephan, Kleber Andre G. (2017), Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis, in CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY, 10(9), e004665.
Uniaxial strain of cardiac tissue parallel to impulse propagation slows conduction more than in the perpendicular direction: untangling the effects of stretch on tissue resistance
Buccarello A., Azzarito M., Michoud F., Lacour S. P., Kucera J. P. (2017), Uniaxial strain of cardiac tissue parallel to impulse propagation slows conduction more than in the perpendicular direction: untangling the effects of stretch on tissue resistance, in ACTA PHYSIOLOGICA, 221(S713), 115-115.
Ephaptic Effects Potentiate the Threshold Behavior of the Cardiac Sodium Current in a High Resolution Mathematical Model of a Narrow Intercellular Cleft
Hichri Echrak, Abriel Hugues, Kucera Jan P. (2017), Ephaptic Effects Potentiate the Threshold Behavior of the Cardiac Sodium Current in a High Resolution Mathematical Model of a Narrow Intercellular Cleft, in BIOPHYSICAL JOURNAL, 112(3), 241-242.
Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model
Jousset Florian, Maguy Ange, Rohr Stephan, Kucera Jan P. (2016), Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model, in FRONTIERS IN PHYSIOLOGY, 7, 496.
Reduced excitability and intercellular coupling lead to slow conduction in cultures of stem cell-derived cardiomyocytes
Azzarito M., Prudat Y., Marcu I. C., Kucera J. P., Ullrich N. D. (2016), Reduced excitability and intercellular coupling lead to slow conduction in cultures of stem cell-derived cardiomyocytes, in ACTA PHYSIOLOGICA, 216, 217-218.
Slow conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes
Kucera Jan P., Prudat Yann, Marcu Irene C., Azzarito Michela, Ullrich Nina D. (2015), Slow conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes, in Frontiers in Cell and Developmental Biology, 3, 58.

Collaboration

Group / person Country
Types of collaboration
Prof. Stéphanie P. Lacour, EPFL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Hugues Abriel, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Workshop on Cardiac Modeling Poster Stretching strands of neonatal murine cardiac myocytes co-cultured with myofibroblasts causes prominent but only transient conduction slowing 15.04.2019 Bad Herrenalb, Germany Buccarello Andrea;
Gordon Research Seminar and Conference on Cardiac Arrhythmia Mechanisms Poster Stretching strands of neonatal murine cardiac myocytes co-cultured with myofibroblasts causes prominent but only transient conduction slowing 30.03.2019 Lucca (Barga), Italy Buccarello Andrea;
Annual Meeting of the LS2 Intersection Cardiovascular Biology Poster Stretching strands of murine cardiac myocytes co-cultured with myofibroblasts causes prominent but only transient conduction slowing 14.03.2019 Fribourg, Switzerland Kucera Jan Pavel; Buccarello Andrea;
Symposium of the Graduate School for Cellular and Biomedical Sciences Poster Stretching strands of murine cardiac myocytes co-cultured with myofibroblasts causes prominent but only transient conduction slowing 31.01.2019 Bern, Switzerland Kucera Jan Pavel; Buccarello Andrea;
Biophysical Society Thematic Meeting: The Heart by Numbers: Integrating Theory, Computation and Experiments to Advance Cardiology Poster Ephaptic effects in the heart: evidence from patch clamp experiments and high-resolution computer models of the intercalated disc 04.09.2018 Berlin, Germany Hichri Echrak; Kucera Jan Pavel;
SIAM Conference on the Life Sciences (LS18) Talk given at a conference Intercellular ephaptic coupling in the heart: myth or reality? 06.08.2018 Minneapolis, United States of America Hichri Echrak; Kucera Jan Pavel;
Yoram Rudy Lab Alumni Reunion Talk given at a conference Intercellular Ephaptic Coupling in the Heart: Myth or Reality? 23.05.2018 St. Louis, United States of America Hichri Echrak; Kucera Jan Pavel;
9th Ascona International Workshop on Cardiomyocyte Biology Poster Ephaptic coupling in the heart: insights from patch clamp experiments and numerical models 22.04.2018 Monte Verità, Switzerland Kucera Jan Pavel; Hichri Echrak;
Annual Meeting of the LS2 Intersection Cardiovascular Biology Talk given at a conference Custom stretchable microelectrode arrays to assess the effects of uniaxial stretch on conduction in cultured cardiomyocyte strands 15.03.2018 Fribourg, Switzerland Kucera Jan Pavel; Hinnen Helene; Buccarello Andrea; Azzarito Michela;
LS2 Life Sciences Annual Meeting Talk given at a conference Ephaptic coupling in the heart is potentiated by the distribution of sodium channels in clusters in the intercalated disc 12.02.2018 Lausanne, Switzerland Hichri Echrak; Kucera Jan Pavel;
Symposium of the Graduate School for Cellular and Biomedical Sciences Talk given at a conference Ephaptic coupling in the heart is potentiated by the distribution of sodium channels in clusters in the intercalated disc 01.02.2018 Bern, Switzerland Hichri Echrak; Kucera Jan Pavel;
Symposium of the Graduate School for Cellular and Biomedical Sciences Poster Directional effects of accurately controlled uniaxial strain on action potential propagation in cultured cardiomyocyte strands 01.02.2018 Bern, Switzerland Kucera Jan Pavel; Hinnen Helene; Azzarito Michela; Buccarello Andrea;
9th TRM Forum on Computer Simulation of Cardiac Function Poster Ephaptic coupling in the heart is potentiated by the distribution of sodium channels in clusters in the intercalated disc 04.12.2017 Lugano, Switzerland Hichri Echrak; Kucera Jan Pavel;
9th TRM Forum on Computer Simulation of Cardiac Function Poster Uniaxial strain of cardiac tissue parallel to impulse propagation slows conduction more than strain in the perpendicular direction 04.12.2017 Lugano, Switzerland Hinnen Helene; Azzarito Michela; Buccarello Andrea; Kucera Jan Pavel;
Day of Clinical Research of the Department of Clinical Research of the University of Bern Poster Uniaxial strain of cardiac tissue parallel to impulse propagation slows conduction more than strain in the perpendicular direction: Untangling the effects of stretch on tissue resistance 31.10.2017 Bern, Switzerland Azzarito Michela; Kucera Jan Pavel; Hinnen Helene; Buccarello Andrea;
Joint Meeting of the Federation of European Physiological Societies Poster Uniaxial strain of cardiac tissue parallel to impulse propagation slows conduction more than in the perpendicular direction: untangling the effects of stretch on tissue resistance 13.09.2017 Wien, Austria Buccarello Andrea; Kucera Jan Pavel; Hinnen Helene;
18th CMi Annual Review Meeting Poster Stretchable electrode arrays for cardiac electrophysiology 02.05.2017 Lausanne, Switzerland Kucera Jan Pavel; Buccarello Andrea; Hinnen Helene;
19th CMi Annual Review Meeting Poster Stretchable electrode arrays for cardiac electrophysiology 02.05.2017 Lausanne, Switzerland Kucera Jan Pavel; Hinnen Helene; Buccarello Andrea;
61st Annual Meeting of the Biophysical Society Poster Ephaptic effects potentiate the threshold behavior of the cardiac sodium current in a high resolution mathematical model of a narrow intercellular cleft 11.02.2017 New Orleans, LA, United States of America Hichri Echrak; Kucera Jan Pavel;
Gordon Conference on Cardiac Arrhythmia Mechanisms Poster Ephaptic effects potentiate the threshold behavior of the cardiac sodium current: insight from a high resolution mathematical model of a narrow intercellular cleft and patch clamp experiments 05.02.2017 Ventura, CA, United States of America Kucera Jan Pavel; Hichri Echrak;
Symposium of the Graduate School for Cellular and Biomedical Sciences Poster Ephaptic effects potentiate the cardiac sodium current threshold behavior in a high resolution mathematical model of a narrow intercellular cleft 02.02.2017 Bern, Switzerland Hichri Echrak; Kucera Jan Pavel;
Day of Clinical Research of the Department of Clinical Research of the University of Bern Poster The threshold behavior of the cardiac sodium current is potentiated by ephaptic effects: insights from a high resolution mathematical model of a narrow intercellular cleft 02.11.2016 Bern, Switzerland Kucera Jan Pavel; Hichri Echrak;
Annual Meeting of the LS2 Section Physiology Talk given at a conference Ephaptic effects potentiate the threshold behaviour of the cardiac sodium current 06.09.2016 Fribourg, Switzerland Kucera Jan Pavel; Hichri Echrak;
40th meeting of the European Working Group on Cardiac Cellular Electrophysiology Poster The threshold behavior of the cardiac sodium current is potentiated by ephaptic effects: insights from a high resolution mathematical model of a narrow intercellular cleft 02.09.2016 Glasgow, Great Britain and Northern Ireland Hichri Echrak; Kucera Jan Pavel;
Channelopathy Meeting Talk given at a conference The activation of the sodium current is potentiated by ephaptic effects in a high resolution mathematical model of the intercalated disc 15.06.2016 Paris, France Kucera Jan Pavel; Hichri Echrak;
Networking Symposium of the UniBE Cardiovascular Research Cluster Poster The activation of the sodium current is potentiated by ephaptic effects in a high resolution mathematical model of the intercalated disc 27.05.2016 Bern, Switzerland Hichri Echrak; Kucera Jan Pavel;
17th CMi Annual Review Meeting Poster Stretchable electrode arrays for cardiac electrophysiology 03.05.2016 Lausanne, Switzerland Azzarito Michela; Kucera Jan Pavel;
2nd International Exploratory Workshop on Computational Tools to Investigate Genetic Channelopathies Talk given at a conference Ephaptic conduction: a myth or a practical reality? 10.01.2016 Beatenberg, Switzerland Kucera Jan Pavel; Hichri Echrak;
2nd International Exploratory Workshop on Computational Tools to Investigate Genetic Channelopathies Talk given at a conference Mathematical modeling of cardiac bioelectrical activity 10.01.2016 Beatenberg, Switzerland Kucera Jan Pavel;
Invited seminar, Institut für Physiologie und Pathophysiologie, University of Heidelberg (Host: Dr. Nina Ullrich) Individual talk Cardiac conduction in heterocellular and heterogeneous tissue: implications for arrhythmogenesis 13.10.2015 Heidelberg, Germany Azzarito Michela; Hinnen Helene; Kucera Jan Pavel;
39th meeting of the European Working Group on Cardiac Cellular Electrophysiology Poster Altered electrical signal propagation and slowed conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes 21.06.2015 Milano, Italy Kucera Jan Pavel; Azzarito Michela;
Gordon Conference on Cardiac Arrhythmia Mechanisms Poster Induced pluripotent stem cells do not restore conduction in cultured strands of fetal murine ventricular myocytes 22.03.2015 Il Ciocco, Lucca, Italy Kucera Jan Pavel; Azzarito Michela;
95. Jahrestagung der Deutschen Physiologischen Gesellschaft Poster Reduced excitability and intercellular coupling lead to slow conduction in cultures of stem cell derived cardiomyocytes 16.03.2015 Lübeck, Germany Azzarito Michela;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Nacht der Forschung der Universität Bern Performances, exhibitions (e.g. for education institutions) 16.09.2017 Bern, Switzerland Kucera Jan Pavel; Hichri Echrak;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Nacht der Forschung der Universität Bern German-speaking Switzerland 2017

Awards

Title Year
Young Investigator Award of the Oetliker Foundation, 3rd prize for an oral presentation at the Annual Meeting of the Swiss Physiological Society 2016

Associated projects

Number Title Start Funding scheme
135016 A systems theory approach to understand cardiac alternans 01.06.2011 Project funding (Div. I-III)
100285 Mathematical modeling and experimental investigation of impulse formation and conduction in cardiac tissue 01.04.2003 Project funding (Div. I-III)
120514 Novel strategies to improve the understanding and diagnosis of cardiac rhythm disorders 01.04.2008 Project funding (Div. I-III)
184707 Understanding the roles of mechanical stretch and of sodium channel nanodomains in cardiac excitation: a multidisciplinary approach 01.05.2019 Project funding (Div. I-III)

Abstract

Heart disease is a major cause of mortality and morbidity. Heart rhythm disorders are frequently and intricately associated with heart disease. Arrhythmias can potentiate heart failure, lead to stroke and cause sudden death. Notwithstanding decades of progress in understanding arrhythmias in clinical practice and basic science, various aspects in this field still require deeper knowledge. In this proposal, we intend to explore two such aspects: A) the interaction between bioelectricity and biomechanics in the generation of arrhythmogenic mechanisms of cardiac tissue excitation and B) ephaptic impulse propagation, an alternate and still controversial mechanism by which cardiac electrical excitation is transmitted from one cell to the next.In these two projects, we will continue combining experimental approaches and computer modeling of cardiac bioelectrical phenomena. This dual approach represents our expertise that we have built over the last 15 years, and the proposed projects are founded on our accomplishments during this period.Project A:How does mechanical deformation affect action potential propagation in cardiac tissue?Cardiac conduction depends on transmembrane and gap junctional currents. However, conduction can also be modulated by deformation of cardiac tissue, especially if excitation and mechanical activity are mismatched, which may occur during heart disease and arrhythmias. Tissue deformation can affect conduction directly by changing the electrical tissue resistance or indirectly via stretch-activated channels or further mechanisms (mechano-electrical coupling).Our aim is to develop a new experimental system permitting the application of controlled deformations to cultures of cardiac cells while recording their electrical activity. We will use a new generation of stretchable microelectrode arrays (collaboration with Prof. Lacour) on which we will grow patterned cultures of rat or mice ventricular myocytes.In a first step, we will characterize the effects of fundamental deformations (uniaxial strain in the directions parallel and perpendicular to impulse propagation) on conduction characteristics. Our principal hypothesis is that strain applied in the direction of impulse propagation vs. strain perpendicular to impulse propagation permits to untangle the effects of changes in tissue resistance from the effects resulting from stretch activated currents and modifications of ion channel function. In a second step, we will investigate the underlying mechanisms (tissue resistance, stretch activated currents in myocytes or fibroblasts, mechanosensitivity of ion currents) using pharmacological interventions and genetic modifications (cells from wild-type vs. connexin 43 knockout mice).These experiments will be paralleled with computer simulations of conduction using a detailed model of tissue architecture incorporating mechanical features, including contractile force generation. This will provide a full picture of the bidirectional interactions between excitation and contraction. Our hypothesis is that microscopic heterogeneities arising from the arrangement of cells, the composition of the tissue (e.g., randomly distributed fibroblasts) and the natural variability of cellular properties lead to sites where conduction is altered more strongly by strain or even blocks.This study is expected to further our understanding of the interactions between electrophysiology and mechanics. This understanding is important to devise more efficient treatments of heart disease and a better prevention of arrhythmias.Project B:Ephaptic conduction in cardiac tissue: myth or practical reality?It is widely accepted that cardiac impulse propagation relies on the flow of current through gap junctions that electrically connect adjacent myocytes. However, an alternate mechanism has been proposed for impulse propagation, especially in situations in which gap junctional coupling is decreased. This mechanism, called “ephaptic transmission”, resides in the fact that the Na+ current through the membrane on one side of a narrow intercellular cleft (e.g., an intercalated disc) causes a negative extracellular potential within the cleft, which translates, on the other side of the cleft, into membrane depolarization and subsequent activation of Na+ channels in the neighbor cell. This mechanism is supported by simulation studies, but, to date, clear experimental evidence at the cellular level is missing. Cardiac ephaptic conduction is therefore a topic of active scientific debate.Our goal is to conduct such proof-of-principle experiments in cell pairs using mammalian cultured cells transfected with different combinations of Na+ and K+ channels that will be apposed to each other while monitoring their electrical activity using patch clamp (collaboration with Prof. Abriel). These experiments will be complemented by corresponding simulations, which will guide us in the interpretation of the experimental results.Because nothing is known about phenomena that may further determine ephaptic interactions within intercellular clefts, we will also develop a computer model of the intercellular cleft / intercalated disc incorporating increasing levels of structural detail in order to examine how ephaptic interactions are modulated by microscopic structural features within a cleft (e.g., non-uniform distribution of gap junctions and Na+ channels, perinexus regions, cleft tortuosity).This study will contribute to resolve the controversy whether ephaptic conduction can really take place in cardiac tissue, a fact which would have profound repercussions on our fundamental understanding of cardiac electrophysiology and the function of cardiac Na+ channels.
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