Project

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A systems theory approach to understand cardiac alternans

Applicant Kucera Jan Pavel
Number 135016
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 01.06.2011 - 30.09.2014
Approved amount 441'082.00
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All Disciplines (3)

Discipline
Cardiovascular Research
Biophysics
Other disciplines of Engineering Sciences

Keywords (11)

cardiac arrhythmias; action potential; cardiac conduction; restitution; alternans; reentry; computer modeling; microelectrode arrays; cardiac cell cultures; ion currents; systems theory

Lay Summary (English)

Lead
Lay summary

Background: Cardiac arrhythmias are frequent complications of heart disease and animportant cause of morbidity and mortality. Cardiac electrical function relieson the action potential (AP), the signal that triggers cellular contraction. Themanner how the AP propagates through the heart is governed by complex dynamics.Understanding these dynamics is primordial to develop new diagnostic,prognostic and therapeutic approaches to arrhythmias.

Project A: New algorithms to characterize and predictalternans 

Alternans, i.e., the beat-to-beat alternation of AP parameters (action potential duration (APD), intracellular increase of Ca2+) can lead to severe arrhythmias (e.g., fibrillation). It results from the interaction of AP parameters during consecutive beats. This interaction is classically described by the dependence of the AP on previous diastolic intervals and APDs. In previous work, we devised a novel method inspired by systems theory to evaluate this interaction by considering cardiac tissue as a “filter” that transforms an input (e.g., the series of pacing intervals) into an output (e.g., the series of APDs). The filter properties are then examined using spectral analysis and transfer functions.
We plan to extend this framework by combining it with eigenmode analysis (a method often applied in physics) to design new approaches for a reliable evaluation and prediction of alternans. These approaches will first be evaluated using computer simulations of the AP and then tested in experiments (using cardiac cell cultures, and, in collaboration with the University of California in Los Angeles, using single cells and whole hearts). Our hypothesis is also that our approach will help to identify the exact mechanisms of alternans. These developments will be important to anticipate the onset of alternans and how it is modulated by pharmacologic agents.

Project B: Does supernormal conduction lead to alternans during reentry?

The dependence of conduction velocity (CV) on the previous diastolic interval (CV restitution) determines conditions promoting reentrant arrhythmias. Usually, premature APs propagate slower than normally paced APs. However, under certain conditions, premature APs can propagate faster than normally paced APs, a phenomenon called supernormal conduction. The effects of supernormal conduction on reentrant excitation have scarcely been studied.
We showed previously that supernormal conduction is intrinsically unstable and potentiates alternans. In this new project, our hypothesis is that supernormal conduction destabilizes reentry and leads to the formation of alternating or more complex excitation patterns, in particular in the case of two reentrant APs in a circuit and in the case of spiral waves. We will examine this hypothesis in experiments (patterned circuits of cardiac cells and cultured monolayers, in which supernormal conduction will be induced by decreasing extracellular [K+]o), paralleled by computer simulations. Our study will provide new insights into supernormal conduction and alternans, and contribute to understand the arrhythmogenic effects of hypokalemia.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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(S707), P22-03.
Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics.
Prudat Yann, Madhvani Roshni V, Angelini Marina, Borgstom Nils P, Garfinkel Alan, Karagueuzian Hrayr S, Weiss James N, de Lange Enno, Olcese Riccardo, Kucera Jan P (2016), Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics., in The Journal of physiology, 594(9), 2537-53.
Altered electrical signal propagation and slowed conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes
Ullrich Nina D., Prudat Yann, Marcu Irene C., Kucera Jan P. (2015), Altered electrical signal propagation and slowed conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes, in Europace, 17(Suppl 3), P492.
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, 58-58.
Nonlinear Behavior of Conduction in Cardiac Tissue with Heterogeneous Expression of Connexin 43
Prudat Yann, Kucera Jan P. (2014), Nonlinear Behavior of Conduction in Cardiac Tissue with Heterogeneous Expression of Connexin 43, in BIOPHYSICAL JOURNAL, 106(2), 120-121.
Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43.
Prudat Yann, Kucera Jan P (2014), Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43., in Journal of Molecular and Cellular Cardiology, 76, 46-54.
What makes the heart rhythm so intricate?
Kucera Jan P (2014), What makes the heart rhythm so intricate?, in Heart Rhythm : the official journal of the Heart Rhythm Society, 11(7), 1220-1.
Changes of Axial Resistance following Mechanical Strain Prevail Over Stretch-Activated Currents in the Modulation of Conduction Velocity in Cardiac Cell Strands
Jousset Florian, Grand Teddy, Rohr Stephan, Kucera Jan P. (2013), Changes of Axial Resistance following Mechanical Strain Prevail Over Stretch-Activated Currents in the Modulation of Conduction Velocity in Cardiac Cell Strands, in BIOPHYSICAL JOURNAL, 104(2), 283-284.
Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias.
Sottas Valentin, Rougier Jean-Sébastien, Jousset Florian, Kucera Jan P, Shestak Anna, Makarov Leonid M, Zaklyazminskaya Elena V, Abriel Hugues (2013), Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias., in Journal of Cardiovascular Electrophysiology, 24(9), 1037-46.
Computational tools to investigate genetic cardiac channelopathies.
Abriel Hugues, de Lange Enno, Kucera Jan P, Loussouarn Gildas, Tarek Mounir (2013), Computational tools to investigate genetic cardiac channelopathies., in Frontiers in Physiology, 4, 390-390.
The propensity to alternans can be quantified in cardiac cells using stochastic pacing
Prudat Yann, Madhvani Roshni V., Borgstrom N. Peter, de Lange Enno, Olcese Riccardo, Kucera Jan P. (2013), The propensity to alternans can be quantified in cardiac cells using stochastic pacing, in Heart Rhythm, 10(5S), P02-90.
Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses.
Lemay Mathieu, de Lange Enno, Kucera Jan P (2012), Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses., in PLoS Computational Biology, 8(3), 1002399-1002399.
Virtual sources and sinks during extracellular field shocks in cardiac cell cultures: effects of source-sink interactions between adjacent tissue boundaries.
Kondratyev Aleksandar A, Didon Jean-Philippe, Hinnen-Oberer Helene, Lemay Mathieu, Kucera Jan P, Kléber Andre G (2012), Virtual sources and sinks during extracellular field shocks in cardiac cell cultures: effects of source-sink interactions between adjacent tissue boundaries., in Circulation. Arrhythmia and Electrophysiology, 5(2), 391-9.
A Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias.
Swan Heikki, Amarouch Mohamed Yassine, Leinonen Jaakko, Marjamaa Annukka, Kucera Jan P, Laitinen-Forsblom Päivi J, Lahtinen Annukka M, Palotie Aarno, Kontula Kimmo, Toivonen Lauri, Abriel Hugues, Widen Elisabeth, A Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias., in Circulation. Cardiovascular Genetics.

Collaboration

Group / person Country
Types of collaboration
Group of R. Olcese / J.N. Weiss, University of California, Los Angeles United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Group of N. Ullrich, University of Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Group of H. Abriel, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Group of S.N. Hatem, Universté Pierre et Marie Curie, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Printemps de la Cardiologie Talk given at a conference Stimulation à cycles aléatoires pour comprendre l'alternance électrique cardiaque : de la théorie à la pratique 01.04.2019 Lille, France Kucera Jan Pavel;
8th Forum of the Theo Rossi di Montelera Foundation on Computer Simulation and Experimental Assessment of Cardiac Electrical Function Talk given at a conference Investigating alternans with stochastic pacing: From theory to practical applications 06.12.2015 Lugano, Switzerland Kucera Jan Pavel;
38th Meeting of the European Working Group on Cardiac Cellular Electrophysiology Talk given at a conference Conduction in tissue with heterogeneous connexin 43 expression: insights from cell cultures and a detailed mathematical model of tissue architecture 20.09.2014 Maastricht, Netherlands Prudat Yann;
19th World Congress on Cardiac Electrophysiology & Cardiac Techniques Poster Cell-to-cell variability of Na+ current density and cell capacitance contributes to the variability of the rate of rise and the amplitude of the action potential during propagation in atrial tissue 18.06.2014 Nice, France Kucera Jan Pavel;
58th Annual Meeting of the Biophysical Society Poster Nonlinear behavior of conduction in cardiac tissue with heterogeneous expression of connexin 43 15.02.2014 San Francisco, United States of America Hinnen Helene; Kucera Jan Pavel; Prudat Yann;
3rd Meeting of the Swiss Society of Cardiology Working Groups AGLA & CVBG, 2014 Poster Cell-to-cell variability of Na+ current density and of cell capacitance contributes to the variability of the rate of rise and the amplitude of the action potential during impulse propagation in atrial tissue 16.01.2014 Fribourg, Switzerland Kucera Jan Pavel;
3rd Meeting of the Swiss Society of Cardiology Working Groups AGLA & CVBG Poster The nonlinear effects of a heterogeneous expression of connexin 43 on cardiac conduction 16.01.2014 Fribourg, Switzerland Kucera Jan Pavel; Prudat Yann; Hinnen Helene;
7th Forum of the Theo Rossi di Montelera Foundation on Computer Simulation and Experimental Assessment of Cardiac Electrical Function Talk given at a conference The nonlinear mixing of normal conduction in normal tissue and slow conduction in uncoupled tissue 01.12.2013 Lugano, Switzerland Kucera Jan Pavel; Prudat Yann; Hinnen Helene;
Inherited Channelopathies Meeting Talk given at a conference Mathematical modeling of cardiac sodium channel mutations and their consequences on myocardial electrical function 21.06.2013 Moscow, Russia Kucera Jan Pavel;
34th Annual Scientific Sessions of the Heart Rhythm Society Poster The propensity to alternans can be quantified in cardiac cells using stochastic pacing 08.05.2013 Denver, United States of America Prudat Yann; Kucera Jan Pavel;
57th Annual Meeting of the Biophysical Society Poster Changes of axial resistance following mechanical strain prevail over stretch-activated currents in the modulation of conduction velocity in cardiac cell strands 02.02.2013 Philadelphia, United States of America Kucera Jan Pavel;
2nd Meeting of the Swiss Society of Cardiology Working Groups AGLA & CVBG Poster Detection of alternans of action potential duration in isolated rabbit ventricular myocytes using an adaptive autoregressive model. 10.01.2013 Bern, Switzerland Kucera Jan Pavel; Hinnen Helene; Prudat Yann;
2nd Meeting of the Swiss Society of Cardiology Working Groups AGLA & CVBG Poster How does stretch of cardiac tissue influence the velocity of action potential propagation? Insights from experiments and computer simulations. 10.01.2013 Bern, Switzerland Kucera Jan Pavel;
Invited lecture at a symposium in Utrecht University (Host: Prof. A.V. Panfilov) Individual talk New pacing protocols and analyses to evaluate cardiac restitution and alternans 29.10.2012 Utrecht, Netherlands Hinnen Helene; Kucera Jan Pavel; Prudat Yann;
Invited seminar, McGill University and University of Montréal (Host: P. Comtois) Individual talk New pacing protocols and analyses to evaluate cardiac restitution and alternans 18.10.2012 Montréal, Canada Prudat Yann; Kucera Jan Pavel; Hinnen Helene;
18th World Congress on Cardiac Electrophysiology & Cardiac Techniques (Cardiostim) Poster Using an adaptive autoregressive model for the early detection of action potential duration alternans 13.06.2012 Nice, France Kucera Jan Pavel; Prudat Yann;
56th Annual Meeting of the Biophysical Society Poster Early detection of action potential duration alternans using an autoregressive model 25.02.2012 San Diego, United States of America Prudat Yann; Kucera Jan Pavel;
6th Forum of the Theo Rossi di Montelera Foundation on Computer Simulation and Experimental Assessment of Cardiac Electrical Function Talk given at a conference Probing cardiac dynamics with random pacing and frequency domain approaches 04.12.2011 Lugano, Switzerland Kucera Jan Pavel;
17th Cardiovascular Biology and Clinical Implications Meeting Talk given at a conference Probing cardiac dynamics with random pacing for the accurate prediction of alternans 06.10.2011 Muntelier, Switzerland Kucera Jan Pavel; Prudat Yann;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Nacht der Forschung, Universität Bern, 2014: Das elektrische Herz German-speaking Switzerland 2014
Talks/events/exhibitions Tag der offenen Tür, Institut für Physiologie, 2012 German-speaking Switzerland 2012

Associated projects

Number Title Start Funding scheme
156738 Bioelectrical-biomechanical interactions in cardiac tissue and ephaptic conduction: two challenging aspects of cardiac electrophysiology 01.10.2014 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)

Abstract

Cardiac arrhythmias are frequent in heart disease and represent an important cause of morbidity and mortality. Despite a wealth of advances in understanding arrhythmias from the level of the ion channel to the level of the whole organ, many challenges remain in both research and clinical practice to obtain an integrated picture of how arrhythmogenic mechanisms interact. Our general aim is to further the integrative understanding of cardiac electrical function. This knowledge is primordial to develop new diagnostic, prognostic and therapeutic approaches to arrhythmias.This proposal is built upon our previous achievements obtained by combining experiments, computer simulations of the action potential (AP) and innovative approaches based on systems theory. This combination is our expertise and we plan to further benefit from it in our new projects.Project A: New algorithms to characterize and predict alternans using frequency-domain analyses of cardiac restitution.Alternans designates the alternation of AP parameters (AP duration (APD), calcium transient) from beat to beat. It leads to dispersion of refractoriness and thus precipitates conduction block and severe reentrant arrhythmias. Alternans results from complex interactions between membrane potential, ion currents and intracellular calcium cycling. The genesis of alternans is linked with cardiac restitution and memory, two notions describing the dependence of AP parameters on the previous diastolic interval (DI), or on several previous DIs and APDs, respectively. However, the understanding of all these interactions is far from complete and efforts are still needed to design approaches for a reliable assessment of the propensity to alternans and its mechanisms.In previous work, we laid the fundament of a novel approach to evaluate restitution in the frequency domain by means of Fourier analysis and transfer functions, which opens new ways to quantify the propensity to alternans and to explore its mechanisms. The aim of this new project is to extend this framework by combining it with a mathematical method called eigenmode analysis in order to design experimental protocols and algorithms for a reliable prediction of alternans that should be superior to those developed so far. These protocols will first be evaluated and optimized using computer models of the AP and then tested and validated in various experimental settings (cardiac cell cultures, and, in collaboration, single cells and whole organ). Further hypotheses are that alternans can be predicted by monitoring other parameters than membrane potential or APD (e.g., calcium transient, mechanical parameters), and that the cause of alternans can be identified in this way. Such identification is important to anticipate in vitro and in vivo the effects of classical antiarrhythmic drugs and of new agents that may be developed in the future to target the cellular calcium handling system.Project B: Does supernormal conduction lead to alternans during reentry?The dependence of conduction velocity (CV) on the previous DI (CV restitution) is an important factor in arrhythmogenesis. It determines conditions promoting reentrant arrhythmias and influences the spatiotemporal dynamics of reentry. Normally, CV depends on the recovery of the sodium current from inactivation, and premature APs propagate slower than normally paced APs. However, under conditions favoring supernormal excitability (e.g., decreased extracellular potassium concentration), there is a range of DIs at which premature APs propagate faster than normally paced APs, a phenomenon called supernormal conduction. While the effects of normal CV restitution on reentry dynamics have been well described, the effects of supernormal conduction have scarcely been studied, and our aim is to investigate these effects.We showed previously that supernormal conduction is intrinsically unstable and potentiates alternans. Our hypothesis is that supernormal conduction induced by low extracellular potassium destabilizes reentry and leads to the formation of alternating or more complex excitation patterns, in particular in the case of two reentrant wavefronts in a circuit and in the case of spiral waves. We will test this hypothesis using a cardiac cell culture model with reduced gap junctional coupling permitting to accommodate two wavefronts in tissue rings and monolayers, and in corresponding computer simulations. Our study will contribute to understand the arrhythmogenic effects of hypokalemia, a common electrolyte abnormality in clinical practice, and provide new insights into dynamics related to supernormal conduction and alternans.
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