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Understanding the roles of mechanical stretch and of sodium channel nanodomains in cardiac excitation: a multidisciplinary approach

English title Understanding the roles of mechanical stretch and of sodium channel nanodomains in cardiac excitation: a multidisciplinary approach
Applicant Kucera Jan Pavel
Number 184707
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 01.05.2019 - 30.04.2023
Approved amount 480'480.00
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All Disciplines (3)

Discipline
Cardiovascular Research
Other disciplines of Engineering Sciences
Biophysics

Keywords (13)

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

Lay Summary (French)

Lead
Les arythmies sont fréquentes dans le cœur malade et sont associés à une morbidité et à une mortalité élevées. Elles sont provoquées par des facteurs modifiant la génération et la propagation du potentiel d’action, le signal électrique qui commande la contraction des cellules du cœur. Les rôles précis de la déformation du tissu cardiaque et de la localisation préférentielle des canaux sodium dans les disques intercalaires (contacts entre les cellules) ne sont pas encore clairement établis.
Lay summary

Contenu et objectifs du travail de recherche

Le premier projet a pour but d’évaluer à l’aide de cultures de cellules cardiaques sur des matrices d’électrodes étirables ainsi que de modèles mathématiques comment différentes déformations du tissu cardiaque influencent la génération et la propagation du potentiel d’action. Nous comptons identifier les mécanismes sous-jacents et évaluer comment les effets des déformations sont modulés par les myofibroblastes (cellules qui prolifèrent lors des affections cardiaques).

Le deuxième projet vise à comprendre à l’aide d’expériences et de modèles comment le courant sodium (essentiel pour le potentiel d’action) est influencé par l’agrégation des canaux sodiques par paires. D’autre part, nous étudierons avec de nouveaux modèles mathématiques comment la propagation du potentiel d’action est influencée par les champs et les potentiels électriques apparaissant dans les espaces intercellulaires des disques intercalaires, là où les canaux sodiques ont tendance à se regrouper.

Contexte scientifique et social du projet de recherche

Notre recherche contribuera de nouvelles connaissances importantes pour la physiologie fondamentale du cœur. Ces connaissances seront utiles aux médecins pour mieux comprendre les mécanismes des arythmies et donc, à long terme, pour concevoir de nouvelles approches pour la prise en charge des patients présentant des arythmies.

Direct link to Lay Summary Last update: 05.04.2019

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
The role of membrane capacitance in cardiac impulse conduction: an optogenetic study with non-excitable cells coupled to cardiomyocytes
Simone Stefano Andrea De, Moyle Sarah, Buccarello Andrea, Dellenbach Christian, Kucera Jan Pavel, Rohr Stephan (2020), The role of membrane capacitance in cardiac impulse conduction: an optogenetic study with non-excitable cells coupled to cardiomyocytes, in Frontiers in Physiology, 11, 194.
Slowing of the time course of acidification decreases the acid-sensing ion channel 1a current amplitude and modulates action potential firing in neurons
Alijevic Omar, Bignucolo Olivier, Hichri Echrak, Peng Zhong, Kucera Jan P., Kellenberger Stephan (2020), Slowing of the time course of acidification decreases the acid-sensing ion channel 1a current amplitude and modulates action potential firing in neurons, in Frontiers in Cellular Neuroscience, 14, 41.
Modeling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules
Vermij Sarah Helena, Abriel Hugues, Kucera Jan Pavel (2019), Modeling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules, in Frontiers in Physiology, 10, 1487.
A modelling framework for the allosteric interactions between sodium channels provides insight into the negative dominance of certain cardiac sodium channel mutations
Kucera Jan P. (2019), A modelling framework for the allosteric interactions between sodium channels provides insight into the negative dominance of certain cardiac sodium channel mutations, in Acta Physiologica, 227(S719), OS 03-08.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
10th TRM Forum on Computer Simulation and Experimental Assessment of Cardiac Function Talk given at a conference (Digital) Twin sodium channels in the heart and the negative dominance of Nav1.5 mutations 08.12.2019 Lugano, Switzerland Kucera Jan Pavel;
98th Meeting of the German Physiological Society Talk given at a conference A modelling framework for the allosteric interactions between sodium channels provides insight into the negative dominance of certain cardiac sodium channel mutations 30.09.2019 Ulm, Germany Kucera Jan Pavel;
Ephaptic Coupling 2019 Conference Talk given at a conference Cardiac Intercellular Coupling: From Weidmann (1921-2005) to Sperelakis (1930-2013) and beyond 05.05.2019 Roanoke, VA, United States of America Kucera Jan Pavel;


Awards

Title Year
Swiss Government Excellence PhD Scholarship (Federal Commission for Scholarships for Foreign Students) awarded to Zoja Selimi, MD, from Kosovo. Title of project: "Ephaptic coupling and interaction between sodium channels in the heart". 2019

Associated projects

Number Title Start Funding scheme
100285 Mathematical modeling and experimental investigation of impulse formation and conduction in cardiac tissue 01.04.2003 Project funding (Div. I-III)
156738 Bioelectrical-biomechanical interactions in cardiac tissue and ephaptic conduction: two challenging aspects of cardiac electrophysiology 01.10.2014 Project funding (Div. I-III)

Abstract

Arrhythmias are frequent in the diseased heart. Reentrant arrhythmias represent an important factor of morbidity and mortality. They can precipitate heart failure, lead to stroke and cause sudden death. Disorders of action potential (AP) propagation, factors favoring conduction block and phenomena susceptible to trigger spontaneous excitations or to alter the rate of the sinoatrial node are mechanistically involved in arrhythmogenesis.In Project A, we will investigate how these factors are modulated by homogeneous and heterogeneous cardiac tissue deformation (strain). In Project B, we will investigate how the sodium (Na+) current (INa), an essential current for AP propagation, is influenced by the formation of Na+ channel dimers and by the distribution of Na+ channels and gap junctions in intercalated discs. Both projects involve a multidisciplinary approach (electrophysiological recordings, in vitro models, biomedical engineering and in silico models) and are a logical follow-up of our previous work.A: How does homogeneous and heterogeneous cardiac tissue strain influence conduction, spontaneous activity, and beat rate variability?Deformation of cardiac tissue influences its electrophysiological properties. This mechano-electrical feedback involves stretch-activated channels in myocytes and/or (myo)fibroblasts, modulation of ion channel function and changes in tissue resistance and capacitance. A deep understanding of how these phenomena influence arrhythmogenesis requires experiments in which strain can be applied to cardiac tissue in a reliably controlled manner while continuously recording its electrical activity. Using our recently developed platform based on cardiac cell cultures grown on stretchable microelectrode arrays in combination with mathematical modeling, we will 1) investigate the kinetic properties of stretch-activated processes and how they influence cardiac conduction, 2) determine whether heterogeneous cardiac tissue strain can cause local conduction delays or block, 3) investigate how cardiac tissue strain influences spontaneous excitations and beat rate variability. Our principal hypotheses are that stretch induces dynamic changes for which new modeling approaches are needed and that sites exposed to the largest strain are the most prone to exhibit conduction disturbances or to cause spontaneous excitations. Our study will contribute to understand how mechanical phenomena influence arrhythmia mechanisms.B: Modeling the interactions between Na+ channels mediated by a-a interactions and extracellular potentials in confined nanodomainsRecent studies showed that Na+ channels form dimers because their a subunits are linked together and that the gating of one channel influences the gating of the other. In addition, our recent work indicates that the previously reported clustering of Na+ channels in intercalated discs exerts major effects on excitation and conduction due to ephaptic interactions caused by large negative extracellular potentials in the intercellular cleft. Therefore, we will 1) implement new modeling concepts in which we will consider pairs of Na+ channels that interact allosterically as the functional units underlying INa and 2) develop high-resolution 3D finite element models of the intercalated disc to address the hypothesis that Na+ channel clustering in nanodomains near gap junction plaques influences cellular excitation and intercellular AP transmission. The models incorporating a-a interactions between Na+ channels will be validated using recordings of single/paired Na+ channel currents, and the intercalated disc models will integrate structural super-resolution microscopy data. Our models will bridge the gap between modeling the single channel and understanding the electrical behavior of the whole cell, and our work will contribute to a better understanding of cardiac electrical excitation at the subcellular scale.Expected value: The insights from both projects are expected to be valuable for both physiologists and cardiologists to better understand arrhythmia mechanisms, with the prospect to devise better approaches for the management of cardiac patients.
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