Project

Back to overview

Novel strategies to improve the understanding and diagnosis of cardiac rhythm disorders

Applicant Kucera Jan Pavel
Number 120514
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 01.04.2008 - 31.05.2011
Approved amount 409'962.00
Show all

Keywords (9)

arrhythmias; computer simulations; microelectrode arrays; electrical restitution; cardiac cell cultures; ion channels; systems theory; action potential; conduction

Lay Summary (English)

Lead
Lay summary
Background: Cardiac function relies on the coordinated propagation of the action potential (AP), the rhythmic electrical signal that triggers the contraction of every cardiac cell. Arrhythmias are frequent complications of heart disease and can potentiate heart failure, lead to stroke and cause sudden death. The AP is an intricate dynamic phenomenon, which relies on the function of ion channels. The complexity of the AP and of cardiac conduction explains why the prevention and treatment of arrhythmias still remains a great challenge. Our research addresses cardiac conduction with an interdisciplinary approach unifying in vitro experiments and computer simulations. In vitro, we use a custom developed system to stimulate and record the electrical activity of cardiac cell cultures with microelectrode arrays. This approach is combined with techniques to pattern the cultures to predefined geometries. In computer simulations, we reconstruct conduction using mathematical models of the cardiac cell. These simulations provide insights into aspects not accessible experimentally. Project A: Conduction velocity and action potential duration depend on one or several previous diastolic or interbeat intervals. This dependence, called "restitution", is an important determinant of the stability of conduction and is involved in the generation of arrhythmias. Our goal is to explore restitution by pacing cardiac tissue at intervals varying randomly from beat to beat and developing novel analyses inspired from systems theory to extract quantitative information regarding restitution and conduction characteristics during random pacing. Our hypothesis is that more information can be obtained compared to conventional pacing protocols. This information will be exploited to derive new strategies to predict the moment and the location at which conduction disturbances occur. The expected developments may form the basis for a future implementation enhancing clinical electrophysiological testing in cardiac patients, permitting to assist diagnostic and therapeutic decisions.Project B: Conduction block is a key arrhythmogenic mechanism. It can result from a reduction of inward membrane currents, a reduction of gap junctional coupling and from tissue inhomogeneities. While computer models are taking into account more and more details about ion currents, computational studies of conduction assume a deterministic behavior of ion currents and thus do not account for the stochastic nature of ion channel gating. Our goal is to explore the consequences of the stochastic channel behavior on conduction. Our hypothesis is that when the safety of conduction becomes critical, small stochastic variations of ion currents may become crucial in determining conduction success or block. To address this hypothesis, we develop a new computer model of conduction incorporating the stochastic channel behavior. Model predictions will be confronted with experiments in cardiac cell cultures. This novel aspect of modeling may open new ways to investigate channel mutations and to explore the possibilities and limits of antiarrhythmic drugs.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

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)
135016 A systems theory approach to understand cardiac alternans 01.06.2011 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

The proper function of the heart relies on the coordinated propagation of the action potential (AP), the electrical signal that triggers the contraction of every cardiac cell. Heart rhythm disorders are frequent complications of heart disease. Arrhythmias can potentiate heart failure, lead to stroke and even cause sudden death. The AP is an intricate dynamic phenomenon, which relies on the function of ion channels in the cell membranes that can open and let ion currents pass through them. The complexity of ion channel function and of cardiac conduction explains why the prevention and treatment of arrhythmias still remains a great challenge.In the two projects outlined below, we will address mechanisms of cardiac conduction with an interdisciplinary approach unifying biological experiments and computer simulations:Experiments: We have developed an in vitro system based on microelectrode arrays to stimulate and record the electrical activity of cardiac cell cultures (rat, mouse). This approach is combined with photolithographic techniques to pattern the cultures to predefined geometries.Simulations: We reconstruct cardiac conduction using mathematical models of the cardiac cell. These computer simulations parallel and complement our experiments and provide insights into complex integrative dynamics not accessible experimentally. Project A: Conduction disorders can be predicted and localized by using a random pacing protocol.Action potential characteristics are highly dependent on the rate with which cardiac tissue is excited. Specifically, conduction velocity (CV) and action potential duration (APD) tightly depend on one or several previous diastolic or interbeat intervals. This rate-dependence, called "restitution", is an important determinant of the stability of conduction. CV and APD restitution relationships (which can be targeted by antiarrhythmic drugs) determine the occurrence of conduction disturbances, the generation of reentrant arrhythmias and the transition between tachycardia and fibrillation. The aim of this project is to explore restitution in second generation mathematical models and in our in vitro model by pacing cardiac tissue at intervals varying randomly from beat to beat. We will develop analytical methods inspired from systems theory in order to extract quantitative information regarding restitution and conduction characteristics (e.g., restitution slopes) during random pacing. Our hypothesis is that more information can be obtained compared to conventional pacing protocols and that this information can be obtained faster. This information will be exploited to derive new strategies to predict the moment and the location at which conduction disturbances occur in cardiac tissue. The expected developments may form the basis for a future implementation enhancing clinical electrophysiological testing. Specifically, it could be rendered possible to predict the occurrence of conduction disturbances in patients with heart disease without the necessity of inducing them and to assist diagnostic and therapeutic decisions.Project B: The stochastic behavior of ion channels determines the fate of the heartbeat.Slow conduction and conduction block are the key mechanisms of reentrant arrhythmias. These two mechanisms result from a reduction of inward membrane currents, a reduction of gap junctional coupling and from tissue inhomogeneities. While computer models of cardiac electrical activity have been taking into account more and more details concerning ion currents, computer model studies of cardiac conduction assume a deterministic behavior of ion currents and thus do not account for the notion that the gating of ion channels is stochastic. The consequences of the stochastic channel behavior on conduction and arrhythmogenesis have never been explored.Our hypothesis is that when the safety of conduction becomes critical, even small variations of ion currents due to this stochastic behavior may become crucial in determining conduction success or block. In the limit, even the opening or closing of one channel may be decisive. This hypothesis will be addressed by developing a new computer model of conduction incorporating the stochastic behavior of channels. The model predictions will be confronted against experiments in cardiomyocyte cultures. This novel aspect of modeling may open new ways to investigate congenital channelopathies and to explore the possibilities and limits of drugs targeting ion channels to prevent and treat arrhythmias.
-